From 81c1f8d10f6c49e836ca62dee6217a2411d8ddd4 Mon Sep 17 00:00:00 2001 From: Chris Mungall Date: Mon, 11 Mar 2024 07:45:55 -0700 Subject: [PATCH 01/21] Fix DOI URLs in publications.rst --- docs/publications.rst | 24 ++++++++++++------------ 1 file changed, 12 insertions(+), 12 deletions(-) diff --git a/docs/publications.rst b/docs/publications.rst index 73135e7c1..52cdbe143 100644 --- a/docs/publications.rst +++ b/docs/publications.rst @@ -23,55 +23,55 @@ Publications | **100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report** | 100,000 Genomes Project Pilot Investigators; Smedley D, ... Caulfield M. | *N Engl J Med. 2021 Nov 11;385(20):1868-1880* -| PMID:34758253 DOI:`10.1056/NEJMoa2035790 `_ +| PMID:34758253 DOI:`10.1056/NEJMoa2035790 `_ | **An Improved Phenotype-Driven Tool for Rare Mendelian Variant Prioritization: Benchmarking Exomiser on Real Patient Whole-Exome Data.** | Cipriani V, Pontikos N, Arno G, Sergouniotis PI, Lenassi E, Thawong P, Danis D, Michaelides M, Webster AR, Moore AT, Robinson PN, Jacobsen JOB, Smedley D. | *Genes (Basel). 2020 Apr 23;11(4):460* -| PMID:32340307 DOI:`10.3390/genes11040460 `_ +| PMID:32340307 DOI:`10.3390/genes11040460 `_ | **A Whole-Genome Analysis Framework for Effective Identification of Pathogenic Regulatory Variants in Mendelian Disease.** | Smedley D, Schubach M, Jacobsen JOB, Köhler S, Zemojtel T, Spielmann M, Jäger M, Hochheiser H, Washington NL, McMurry JA, Haendel MA, Mungall CJ, Lewis SE, Groza T, Valentini G, Robinson PN. | *The American Journal of Human Genetics 2016;99;3;595-606* -| PMID:27569544 DOI:`10.1016/j.ajhg.2016.07.005 `_ +| PMID:27569544 DOI:`10.1016/j.ajhg.2016.07.005 `_ | **Phenotype-driven strategies for exome prioritization of human Mendelian disease genes.** | Smedley D, Robinson PN. | *Genome Medicine 2015, 7(1):81* -| PMID:26229552 DOI:`10.1186/s13073-015-0199-2 `_ +| PMID:26229552 DOI:`10.1186/s13073-015-0199-2 `_ | **Next-generation diagnostics and disease-gene discovery with the Exomiser.** | Smedley D, Jacobsen JO, Jäger M, Köhler S, Holtgrewe M et al. | *Nature protocols 2015;10;12;2004-15* -| PMID:26562621 DOI:`10.1038/nprot.2015.124 `_ +| PMID:26562621 DOI:`10.1038/nprot.2015.124 `_ | **Computational evaluation of exome sequence data using human and model organism phenotypes improves diagnostic efficiency.** | Bone WP, Washington NL, Buske OJ, Adams DR, Davis J et al. | *Genetics in medicine : official journal of the American College of Medical Genetics 2015* -| PMID:26562225 DOI:`10.1038/gim.2015.137 `_ +| PMID:26562225 DOI:`10.1038/gim.2015.137 `_ | **Walking the interactome for candidate prioritization in exome sequencing studies of Mendelian diseases.** | Smedley D, Köhler S, Czeschik JC, Amberger J, Bocchini C et al. | *Bioinformatics (Oxford, England) 2014;30;22;3215-22* -| PMID:25078397 DOI:`10.1093/bioinformatics/btu508 `_ +| PMID:25078397 DOI:`10.1093/bioinformatics/btu508 `_ | **Effective diagnosis of genetic disease by computational phenotype analysis of the disease-associated genome.** | Zemojtel T, Köhler S, Mackenroth L, Jäger M, Hecht J et al. | *Science translational medicine 2014;6;252;252ra123* -| PMID:25186178 DOI:`10.1126/scitranslmed.3009262 `_ +| PMID:25186178 DOI:`10.1126/scitranslmed.3009262 `_ | **Improved exome prioritization of disease genes through cross-species phenotype comparison.** | Robinson PN, Köhler S, Oellrich A, Sanger Mouse Genetics Project, Wang K et al. | *Genome research 2014;24;2;340-8* -| PMID:24162188 DOI:`10.1101/gr.160325.113 `_ +| PMID:24162188 DOI:`10.1101/gr.160325.113 `_ Collaborations @@ -88,17 +88,17 @@ Publications for other projects and resources in which the Exomiser is used as a | **Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience.** | Gall T, Valkanas E, BelloC, Markello T, Adams C, Bone WP, Brandt AJ, Brazill JM, Carmichael L, Davids M, Davis J, Diaz-Perez Z, Draper D, Elson J, Flynn ED, Godfrey R, Groden C, Hsieh CK, Fischer R, Golas GA, Guzman J, Huang Y, Kane MS, Lee E, Li C, Links AE, Maduro V, Malicdan MCV, Malik FS, Nehrebecky M, Park J, Pemberton P, Schaffer K, Simeonov D, Sincan M, Smedley D, Valivullah Z, Wahl C, Washington N, Wolfe LA, Xu K, Zhu Y, Gahl WA, Tifft CJ, Toro C, Adams DR, He M, Robinson PN, Haendel MA, Zhai RG, Boerkoel CF. | *Front Med (Lausanne). 2017;4 62* -| PMID: 28603714 DOI:`10.3389/fmed.2017.00062 `_ +| PMID: 28603714 DOI:`10.3389/fmed.2017.00062 `_ | **PhenomeCentral: A Portal for Phenotypic and Genotypic Matchmaking of Patients with Rare Genetic Diseases.** | Orion J. Buske, Marta Girdea, Sergiu Dumitriu, Bailey Gallinger, Taila Hartley, Heather Trang, Andriy Misyura, Tal Friedman, Chandree Beaulieu, William P. Bone, Amanda E. Links, Nicole L. Washington, Melissa A. Haendel, Peter N. Robinson, Cornelius F. Boerkoel, David Adams, William A. Gahl, Kym M. Boycott, Michael Brudno. | *Human Mutation 2015, 36(10):931-940* -| PMID: 26251998 DOI:`10.1002/humu.22851 `_ +| PMID: 26251998 DOI:`10.1002/humu.22851 `_ | **Phenopolis: an open platform for harmonization and analysis of genetic and phenotypic data.** | Nikolas Pontikos, Jing Yu, Ismail Moghul, Lucy Withington, Fiona Blanco-Kelly, Tom Vulliamy, Tsz Lun, Ernest Wong, Cian Murphy, Valentina Cipriani, Alessia Fiorentino, Gavin Arno, Daniel Greene, Julius OB Jacobsen, Tristan Clark, David S. Gregory, Andrea M. Nemeth, Stephanie Halford, Chris F. Inglehearn, Susan Downes, Graeme C. Black, Andrew R. Webster, Alison J. Hardcastle, UKIRDC, Vincent Plagnol. | *Bioinformatics 2017,33(15):2421-2423* -| PMID: 28334266 DOI:`10.1093/bioinformatics/btx147 `_ +| PMID: 28334266 DOI:`10.1093/bioinformatics/btx147 `_ From edb173d6a48e87660f3061e4a71dcf2fbcc7015b Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Fri, 3 May 2024 14:18:00 +0100 Subject: [PATCH 02/21] Updates to enable spliceAI ingest into Exomiser variant database. Add SpliceAiAlleleResource and SpliceAiAlleleParser classes to exomiser-data-genome Update VariantDatabaseBuildRunner internals for better readability Update HgNNConfig to add new `splice-ai` resource Update BuildCommand to add `splice-ai` to variant build fallback value Update exomiser-data-genome application.properties to add pre-filtered `hg19.splice-ai` and `hg38.splice-ai` resources --- .../exomiser/data/genome/BuildCommand.java | 2 +- .../genome/VariantDatabaseBuildRunner.java | 15 +- .../data/genome/config/Hg19Config.java | 5 + .../data/genome/config/Hg38Config.java | 5 + .../model/parsers/SpliceAiAlleleParser.java | 34 +++++ .../resource/SpliceAiAlleleResource.java | 14 ++ .../src/main/resources/application.properties | 8 ++ .../VariantDatabaseBuildRunnerTest.java | 48 +++++++ .../parsers/SpliceAiAlleleParserTest.java | 131 ++++++++++++++++++ 9 files changed, 256 insertions(+), 6 deletions(-) create mode 100644 exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParser.java create mode 100644 exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/resource/SpliceAiAlleleResource.java create mode 100644 exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunnerTest.java create mode 100644 exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParserTest.java diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/BuildCommand.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/BuildCommand.java index d52e38c8a..2bc3cd167 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/BuildCommand.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/BuildCommand.java @@ -74,7 +74,7 @@ public class BuildCommand implements Callable { private Path buildClinVar; @Option(names = "--transcripts", converter = TranscriptSourceConverter.class, split = ",", arity = "0..1", fallbackValue = "ensembl,refseq,ucsc", description = "List of transcript databases to build. If specified without parameter, will build all sources: ${FALLBACK-VALUE}") private List transcriptSources; - @Option(names = "--variants", split = ",", arity = "0..1", fallbackValue = "esp,exac,uk10k,topmed,dbsnp,gnomad-exome,gnomad-genome,gnomad-mito,alfa,dbnsfp", description = "List of variant data sources to build. If specified without parameter, will build all sources: ${FALLBACK-VALUE}") + @Option(names = "--variants", split = ",", arity = "0..1", fallbackValue = "esp,exac,uk10k,topmed,dbsnp,gnomad-exome,gnomad-genome,gnomad-mito,alfa,dbnsfp,splice-ai", description = "List of variant data sources to build. If specified without parameter, will build all sources: ${FALLBACK-VALUE}") private List variantSources; @Option(names = "--genome", description = "Flag to trigger building of genome data.") private boolean buildGenome; diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunner.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunner.java index 0acc7f170..dfb99e5fc 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunner.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunner.java @@ -20,12 +20,8 @@ package org.monarchinitiative.exomiser.data.genome; -import org.h2.mvstore.MVMap; import org.h2.mvstore.MVStore; import org.h2.mvstore.MVStoreTool; -import org.monarchinitiative.exomiser.core.genome.dao.serialisers.MvStoreUtil; -import org.monarchinitiative.exomiser.core.proto.AlleleProto.AlleleKey; -import org.monarchinitiative.exomiser.core.proto.AlleleProto.AlleleProperties; import org.monarchinitiative.exomiser.data.genome.indexers.Indexer; import org.monarchinitiative.exomiser.data.genome.indexers.MvStoreAlleleIndexer; import org.monarchinitiative.exomiser.data.genome.model.Allele; @@ -58,7 +54,7 @@ public VariantDatabaseBuildRunner(BuildInfo buildInfo, Path buildPath, List hg19AlleleResources() { // ExAC removed as this is part of gnomad-exomes alleleResources.put("esp", espAlleleResource()); alleleResources.put("dbnsfp", dbnsfpAlleleResource()); + alleleResources.put("splice-ai", spliceAiAlleleResource()); // CLinVar removed - now handled as a separate data source return alleleResources.build(); } + private AlleleResource spliceAiAlleleResource() { + return alleleResource(SpliceAiAlleleResource.class, "hg19.splice-ai"); + } + public DbSnpAlleleResource dbSnpAlleleResource() { return alleleResource(DbSnpAlleleResource.class, "hg19.dbsnp"); } diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java index 0ede208a6..dc165fd54 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java @@ -90,11 +90,16 @@ public Map hg38AlleleResources() { // ExAC removed as this is part of gnomad-exomes v2.1 // ESP removed as this is part of gnomad-exomes v4 alleleResources.put("dbnsfp", dbnsfpAlleleResource()); + alleleResources.put("splice-ai", spliceAiAlleleResource()); // CLinVar removed - now handled as a separate data source return alleleResources.build(); } + private AlleleResource spliceAiAlleleResource() { + return alleleResource(SpliceAiAlleleResource.class, "hg38.splice-ai"); + } + public DbSnpAlleleResource dbSnpAlleleResource() { return alleleResource(DbSnpAlleleResource.class, "hg38.dbsnp"); } diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParser.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParser.java new file mode 100644 index 000000000..6f9046263 --- /dev/null +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParser.java @@ -0,0 +1,34 @@ +package org.monarchinitiative.exomiser.data.genome.model.parsers; + +import org.monarchinitiative.exomiser.core.genome.Contigs; +import org.monarchinitiative.exomiser.core.proto.AlleleProto; +import org.monarchinitiative.exomiser.data.genome.model.Allele; + +import java.util.List; + +public class SpliceAiAlleleParser implements AlleleParser { + @Override + public List parseLine(String line) { + if (line.startsWith("#")) { + // comment line. + return List.of(); + } + var allele = parseAllele(line); + return List.of(allele); + } + + private Allele parseAllele(String line) { + String[] fields = line.split("\t"); + if (fields.length != 5) { + throw new IllegalStateException("Expected 5 fields but found " + fields.length + " in line " + line); + } + int chr = Contigs.parseId(fields[0]); // 1..22,X,Y,MT + int start = Integer.parseInt(fields[1]); + String ref = fields[2]; + String alt = fields[3]; + float score = Float.parseFloat(fields[4]); + Allele allele = new Allele(chr, start, ref, alt); + allele.addPathogenicityScore(AlleleProto.PathogenicityScore.newBuilder().setPathogenicitySource(AlleleProto.PathogenicitySource.SPLICE_AI).setScore(score).build()); + return allele; + } +} diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/resource/SpliceAiAlleleResource.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/resource/SpliceAiAlleleResource.java new file mode 100644 index 000000000..8184b85ff --- /dev/null +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/resource/SpliceAiAlleleResource.java @@ -0,0 +1,14 @@ +package org.monarchinitiative.exomiser.data.genome.model.resource; + +import org.monarchinitiative.exomiser.data.genome.model.archive.TabixArchive; +import org.monarchinitiative.exomiser.data.genome.model.parsers.SpliceAiAlleleParser; + +import java.net.URL; +import java.nio.file.Path; + +public class SpliceAiAlleleResource extends AbstractAlleleResource { + + public SpliceAiAlleleResource(String name, URL resourceUrl, Path resourcePath) { + super(name, resourceUrl, new TabixArchive(resourcePath), new SpliceAiAlleleParser()); + } +} diff --git a/exomiser-data-genome/src/main/resources/application.properties b/exomiser-data-genome/src/main/resources/application.properties index b1e64131d..400c4f795 100644 --- a/exomiser-data-genome/src/main/resources/application.properties +++ b/exomiser-data-genome/src/main/resources/application.properties @@ -62,6 +62,10 @@ hg19.uk10k.file-dir=${hg19.variant-dir} hg19.dbnsfp.file-name=dbNSFP4.5a.zip hg19.dbnsfp.file-url=ftp://dbnsfp:dbnsfp@dbnsfp.softgenetics.com/ hg19.dbnsfp.file-dir=${hg19.variant-dir} +# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg19.vcf.gz to only include variants max(delta_score) >= 2.0 +hg19.splice-ai.file-name=spliceai_max_delta_scores_non_zero.masked.snv.hg19.vcf.gz +hg19.splice-ai.file-url=file://${hg19.variant-dir} +hg19.splice-ai.file-dir=${hg19.variant-dir} #hg38 hg38.variant-dir=${build-dir}/hg38/variants @@ -106,3 +110,7 @@ hg38.uk10k.file-dir=${hg38.variant-dir} hg38.dbnsfp.file-name=${hg19.dbnsfp.file-name} hg38.dbnsfp.file-url=${hg19.dbnsfp.file-url} hg38.dbnsfp.file-dir=${hg19.variant-dir} +# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg38.vcf.gz to only include variants max(delta_score) >= 2.0 +hg38.splice-ai.file-name=spliceai_max_delta_scores_non_zero.masked.snv.hg38.vcf.gz +hg38.splice-ai.file-url=file://${hg38.variant-dir} +hg38.splice-ai.file-dir=${hg38.variant-dir} diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunnerTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunnerTest.java new file mode 100644 index 000000000..cf59518fc --- /dev/null +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/VariantDatabaseBuildRunnerTest.java @@ -0,0 +1,48 @@ +package org.monarchinitiative.exomiser.data.genome; + + +import org.junit.jupiter.api.Disabled; +import org.junit.jupiter.api.Test; +import org.junit.jupiter.api.io.TempDir; +import org.monarchinitiative.exomiser.core.genome.GenomeAssembly; +import org.monarchinitiative.exomiser.data.genome.model.AlleleResource; +import org.monarchinitiative.exomiser.data.genome.model.BuildInfo; +import org.monarchinitiative.exomiser.data.genome.model.parsers.DbNsfpColumnIndex; +import org.monarchinitiative.exomiser.data.genome.model.resource.DbNsfp4AlleleResource; +import org.monarchinitiative.exomiser.data.genome.model.resource.SpliceAiAlleleResource; + +import java.io.IOException; +import java.nio.file.Files; +import java.nio.file.Path; +import java.util.List; + +import static org.hamcrest.MatcherAssert.assertThat; +import static org.hamcrest.Matchers.*; + +class VariantDatabaseBuildRunnerTest { + + @Test + void testBuild(@TempDir Path tempDir) throws IOException { + BuildInfo buildInfo = BuildInfo.of(GenomeAssembly.HG38, "2404"); + List alleleResources = List.of(new DbNsfp4AlleleResource("hg38.dbnsfp", null, Path.of("src/test/resources/dbNSFP4.0_test.zip"), DbNsfpColumnIndex.HG38)); + VariantDatabaseBuildRunner instance = new VariantDatabaseBuildRunner(buildInfo, tempDir, alleleResources); + instance.run(); + Path variantDatabase = instance.variantDatabasePath(); + assertThat(Files.exists(variantDatabase), is(true)); + assertThat(Files.size(variantDatabase), greaterThan(0L)); + } + + @Disabled("Manual testing") + @Test + void manualTestBuild() throws IOException { + BuildInfo buildInfo = BuildInfo.of(GenomeAssembly.HG19, "2404"); + Path buildPath = Path.of("/data/exomiser-build/"); + List alleleResources = List.of(new SpliceAiAlleleResource("hg19.splice-ai", null, buildPath.resolve("spliceai_max_delta_scores_sig_only.masked.snv.hg19.vcf.gz"))); + VariantDatabaseBuildRunner instance = new VariantDatabaseBuildRunner(buildInfo, buildPath, alleleResources); + instance.run(); + Path variantDatabase = instance.variantDatabasePath(); + assertThat(Files.exists(variantDatabase), is(true)); + assertThat(Files.size(variantDatabase), greaterThan(0L)); + } + +} \ No newline at end of file diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParserTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParserTest.java new file mode 100644 index 000000000..c2baa7285 --- /dev/null +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/SpliceAiAlleleParserTest.java @@ -0,0 +1,131 @@ +package org.monarchinitiative.exomiser.data.genome.model.parsers; + +import htsjdk.samtools.util.BlockCompressedOutputStream; +import org.junit.jupiter.api.Disabled; +import org.junit.jupiter.api.Test; +import org.monarchinitiative.exomiser.core.genome.Contigs; +import org.monarchinitiative.exomiser.core.proto.AlleleProto; +import org.monarchinitiative.exomiser.data.genome.model.Allele; +import org.slf4j.Logger; +import org.slf4j.LoggerFactory; + +import java.io.*; +import java.nio.file.Files; +import java.nio.file.Path; +import java.util.List; +import java.util.zip.GZIPInputStream; + +import static org.hamcrest.MatcherAssert.assertThat; +import static org.hamcrest.Matchers.equalTo; + +class SpliceAiAlleleParserTest { + + @Test + void parseNonSexChrLine() { + String line = "10\t12345\tA\tC\t1.0"; + List result = new SpliceAiAlleleParser().parseLine(line); + Allele expected = new Allele(10, 12345, "A", "C"); + expected.addPathogenicityScore(AlleleProto.PathogenicityScore.newBuilder().setPathogenicitySource(AlleleProto.PathogenicitySource.SPLICE_AI).setScore(1f).build()); + assertThat(result, equalTo(List.of(expected))); + } + + @Test + void parseSexChrLine() { + String line = "X\t12345\tA\tC\t1.0"; + List result = new SpliceAiAlleleParser().parseLine(line); + Allele expected = new Allele(23, 12345, "A", "C"); + expected.addPathogenicityScore(AlleleProto.PathogenicityScore.newBuilder().setPathogenicitySource(AlleleProto.PathogenicitySource.SPLICE_AI).setScore(1f).build()); + assertThat(result, equalTo(List.of(expected))); + } + + /** + * This is a one-off method to prepare the SpliceAI data by selecting only the max score from the DL/DG/AL/AG scores + * >= minScore. This is recommended as >= 0.2 for high recall, increasing to 0.5 as a default and 0.8 for high-precision. + * confidence. Jaganathan et al, Cell 2019 and https://github.com/Illumina/SpliceAI + * + *
+ * Delta score of a variant, defined as the maximum of (DS_AG, DS_AL, DS_DG, DS_DL), ranges from 0 to 1 and can be interpreted as the probability of the variant being splice-altering. In the paper, a detailed characterization is provided for 0.2 (high recall), 0.5 (recommended), and 0.8 (high precision) cutoffs. Delta position conveys information about the location where splicing changes relative to the variant position (positive values are downstream of the variant, negative values are upstream). + *
+ * + * These annotations are free for academic and not-for-profit use; other use requires a commercial license from Illumina, Inc. + * + **/ + @Disabled + @Test + void prepareSpliceAiData() { + Path dataPath = Path.of("/home/hhx640/Documents/exomiser-build/"); + Path inFile = dataPath.resolve("spliceai_scores.masked.snv.hg19.vcf.gz"); + Path outFile = dataPath.resolve("spliceai_max_delta_scores_non_zero.masked.snv.hg19.vcf.gz"); + // the ACMG guidelines for use of SpliceAI scores recommend anything under 0.1 to be scored BP4 and over 0.2 PP3 + // so, we're using that cutoff here. This means that any SNP with no score in the database can be considered as + // not impacting splicing. + float minScore = 0.1f; + SpliceAiMaxDeltaScoreParser.build(inFile, outFile, minScore); + } + + private static class SpliceAiMaxDeltaScoreParser { + + private static final Logger logger = LoggerFactory.getLogger(SpliceAiMaxDeltaScoreParser.class); + + public static void build(Path spliceAiInputPath, Path outputBgZipPath, float minScore) { + long count = 0; + logger.info("Parsing SpliceAI scores from {} with a maximum delta score >= {}", spliceAiInputPath.getFileName(), minScore); + try (BufferedReader bufferedReader = new BufferedReader(new InputStreamReader(new GZIPInputStream(Files.newInputStream(spliceAiInputPath)))); + BufferedWriter bufferedWriter = new BufferedWriter(new OutputStreamWriter(new BlockCompressedOutputStream(outputBgZipPath.toFile(), 6))); + ) { + for (String line; (line = bufferedReader.readLine()) != null; ) { + if (line.startsWith("##")) { + bufferedWriter.write(line); + bufferedWriter.newLine(); + continue; + } + if (line.startsWith("#")) { + bufferedWriter.write("#CHROM\tPOS\tREF\tALT\tSPLICE_AI_MAX_DELTA_SCORE"); + bufferedWriter.newLine(); + continue; + } + //##INFO= + //1 69092 . T A . . SpliceAI=A|OR4F5|0.00|0.00|0.22|0.00|2|41|1|23 + String[] fields = line.split("\t"); + if (fields.length != 8) { + throw new IllegalArgumentException("Expected 8 fields but found " + fields.length + " in line " + line); + } + String contig = Contigs.toString(Contigs.parseId(fields[0])); // 1..22,X,Y,MT + int start = Integer.parseInt(fields[1]); + String ref = fields[3]; + String alt = fields[4]; + float score = parseSpliceAiScore(fields[7]); + // hg38 contains some oddly named unplaced contigs which end up with a contig of 0 and this leads to + // failed tabix indexing, so check and remove these. + if (!contig.equals("0") && score >= minScore) { + count++; + if (count % 1_000_000 == 0) { + logger.info("Current contig {} - written {} variants. Current: {}-{}-{}-{} SpliceAI={}", contig, count, contig, start, ref, alt, score); + } + String outLine = contig + "\t" + start + "\t" + ref + "\t"+ alt + "\t" + score; + bufferedWriter.write(outLine); + bufferedWriter.newLine(); + } + } + logger.info("Done - written {} variants", count); + } catch (IOException e) { + logger.error("Unable to write file " + outputBgZipPath, e); + } + } + + static float parseSpliceAiScore(String info) { + String[] fields = info.split("\\|"); + // SpliceAIv1.3 variant annotation. These include delta scores (DS) and delta positions (DP) for acceptor gain (AG), + // acceptor loss (AL), donor gain (DG), and donor loss (DL). + // Format: ALLELE|SYMBOL|DS_AG|DS_AL|DS_DG|DS_DL|DP_AG|DP_AL|DP_DG|DP_DL" + // SpliceAI=A|OR4F5|0.00|0.00|0.22|0.00|2|41|1|23 + // we want the max delta score for gain or loss + float max = 0f; + for (int i = 2; i < 6; i++) { + max = Math.max(max, Float.parseFloat(fields[i])); + } + return max; + } + + } +} \ No newline at end of file From b0e694e7da19f4ea9d67ec1cc685c86302c88fa2 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Fri, 3 May 2024 14:24:44 +0100 Subject: [PATCH 03/21] Changes to enable SpliceAI PP3 and other splicing-related ACMG assignments Add new AcmgSpliceEvidenceAssigner class Add new AcmgPVS1EvidenceAssigner class Add new AcmgEvidence.Builder.containsWithEvidence method Add @Nullable to PathogenicityData.pathogenicityScore method Update VariantDataServiceImpl to remove hard filter on scores for synonymous variants in order to allow SpliceAI scores to come through for cryptic splice sites. Add Docs to SpliceAiScore Remove SYNONYMOUS and SPLICE_REGION variants from NON_EXONIC_EFFECTS in exomiser-web SubmitJobController --- .../util/acmg/Acmg2015EvidenceAssigner.java | 183 ++++++++------- .../core/analysis/util/acmg/AcmgEvidence.java | 4 + .../util/acmg/AcmgPVS1EvidenceAssigner.java | 161 +++++++++++++ .../util/acmg/AcmgSpliceEvidenceAssigner.java | 212 ++++++++++++++++++ .../core/genome/VariantDataServiceImpl.java | 7 +- .../pathogenicity/PathogenicityData.java | 2 + .../model/pathogenicity/SpliceAiScore.java | 17 ++ .../acmg/Acmg2015EvidenceAssignerTest.java | 13 +- .../analysis/util/acmg/AcmgEvidenceTest.java | 9 + .../web/controller/SubmitJobController.java | 2 - 10 files changed, 515 insertions(+), 95 deletions(-) create mode 100644 exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java create mode 100644 exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java index 78d3466ce..1963c95a1 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java @@ -46,6 +46,7 @@ import java.util.regex.Matcher; import java.util.regex.Pattern; +import static de.charite.compbio.jannovar.annotation.VariantEffect.*; import static org.monarchinitiative.exomiser.core.analysis.util.acmg.AcmgCriterion.*; /** @@ -158,7 +159,7 @@ public AcmgEvidence assignVariantAcmgEvidence(VariantEvaluation variantEvaluatio boolean hasCompatibleDiseaseMatches = !compatibleDiseaseMatches.isEmpty(); // PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" - assignPVS1(acmgEvidenceBuilder, variantEvaluation, modeOfInheritance, knownDiseases); + AcmgPVS1EvidenceAssigner.assignPVS1(acmgEvidenceBuilder, variantEvaluation, probandSex, modeOfInheritance, knownDiseases); // ignore non-missense, truncating, splice or mitochondrial variants if (isMissenseOrInframeIndel(variantEvaluation.getVariantEffect()) && variantEvaluation.contigId() != 25) { @@ -175,6 +176,10 @@ public AcmgEvidence assignVariantAcmgEvidence(VariantEvaluation variantEvaluatio assignPM1(acmgEvidenceBuilder, variantEvaluation, localClinVarData); // TODO: PM1/BP3 "In-frame deletions/insertions in a repetitive region without a known function" - requires domain information. } + // apply PVS1, PS1, PP3, BP4, BP7 to splice region variants according to "Using the ACMG/AMP framework to capture + // evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup" + // https://doi.org/10.1016/j.ajhg.2023.06.002 + AcmgSpliceEvidenceAssigner.assignSpliceEvidence(acmgEvidenceBuilder, variantEvaluation, modeOfInheritance, knownDiseases, clinVarDao); if (pedigree.containsId(probandId)) { Individual proband = pedigree.getIndividualById(probandId); @@ -210,88 +215,88 @@ public AcmgEvidence assignVariantAcmgEvidence(VariantEvaluation variantEvaluatio return acmgEvidenceBuilder.build(); } - /** - * PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" - */ - private void assignPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List knownDiseases) { - // TODO: add new method - gene.getAssociatedDiseases() - // also need ClinvarCache.getClinvarDataForGene(GeneIdentifier geneIdentifier) - - // Certain types of variants (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon - // deletion) can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of tran- - // scription or nonsense-mediated decay of an altered transcript. One must, however, exercise caution when classifying these - // variants as pathogenic by considering the following principles: - // (i) When classifying such variants as pathogenic, one must ensure that null variants are a known mechanism of - // pathogenicity consistent with the established inheritance pattern for the disease. For example, there are genes for - // which only heterozygous missense variants cause disease and null variants are benign in a heterozygous state (e.g., - // many hypertrophic cardiomyopathy genes). A novel heterozygous nonsense variant in the MYH7 gene would - // not be considered pathogenic for dominant hypertrophic cardiomyopathy based solely on this evidence, whereas a - // novel heterozygous nonsense variant in the CFTR gene would likely be considered a recessive pathogenic variant. - // Caveats: - // • Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7) - // • Use caution interpreting LOF variants at the extreme 3′ end of a gene - // • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact - // • Use caution in the presence of multiple transcripts - - GeneConstraint geneContraint = GeneConstraints.geneConstraint(variantEvaluation.getGeneSymbol()); - // Should this be using the hasCompatibleDiseaseMatches variable? - boolean inGeneWithKnownDiseaseAssociations = !knownDiseases.isEmpty(); - if (inGeneWithKnownDiseaseAssociations && isLossOfFunctionEffect(variantEvaluation.getVariantEffect()) - && (modeOfInheritance == ModeOfInheritance.ANY - || compatibleWithRecessive(modeOfInheritance) - || compatibleWithDominant(modeOfInheritance) && (geneContraint != null && geneContraint.isLossOfFunctionIntolerant()) - ) - ) { - if (variantEvaluation.hasTranscriptAnnotations()) { - TranscriptAnnotation transcriptAnnotation = variantEvaluation.getTranscriptAnnotations().get(0); - if (predictedToLeadToNmd(transcriptAnnotation)) { - acmgEvidenceBuilder.add(PVS1); - } else { - // Not predicted to lead to NMD? Downgrade to STRONG - acmgEvidenceBuilder.add(PVS1, Evidence.STRONG); - } - } else { - // shouldn't happen that there are no transcript annotations, but just in case... - acmgEvidenceBuilder.add(PVS1, Evidence.STRONG); - } - } - } - - private boolean isLossOfFunctionEffect(VariantEffect variantEffect) { - return variantEffect == VariantEffect.START_LOST - || variantEffect == VariantEffect.STOP_LOST - || variantEffect == VariantEffect.STOP_GAINED - || variantEffect == VariantEffect.FRAMESHIFT_ELONGATION - || variantEffect == VariantEffect.FRAMESHIFT_TRUNCATION - || variantEffect == VariantEffect.FRAMESHIFT_VARIANT - || variantEffect == VariantEffect.SPLICE_ACCEPTOR_VARIANT - || variantEffect == VariantEffect.SPLICE_DONOR_VARIANT - || variantEffect == VariantEffect.EXON_LOSS_VARIANT; - } - - private boolean predictedToLeadToNmd(TranscriptAnnotation transcriptAnnotation) { - // predicted to lead to NMD if in last exon or last 50bp of penultimate exon, or in single exon transcript - boolean notInLastExon = transcriptAnnotation.getRank() < transcriptAnnotation.getRankTotal(); - boolean isSingleExonTranscript = transcriptAnnotation.getRankTotal() == 1; - return transcriptAnnotation.getRankType() == TranscriptAnnotation.RankType.EXON && (notInLastExon || isSingleExonTranscript); - } - - private boolean compatibleWithRecessive(ModeOfInheritance modeOfInheritance) { - if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_RECESSIVE) { - return true; - } - return probandSex == Individual.Sex.FEMALE && modeOfInheritance == ModeOfInheritance.X_RECESSIVE; - } - - private boolean compatibleWithDominant(ModeOfInheritance modeOfInheritance) { - if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_DOMINANT) { - return true; - } - if (probandSex == Individual.Sex.MALE && (modeOfInheritance == ModeOfInheritance.X_RECESSIVE || modeOfInheritance == ModeOfInheritance.X_DOMINANT)) { - return true; - } - return (probandSex == Individual.Sex.FEMALE || probandSex == Individual.Sex.UNKNOWN) && modeOfInheritance == ModeOfInheritance.X_DOMINANT; - } +// /** +// * PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" +// */ +// private void assignPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List knownDiseases) { +// // TODO: add new method - gene.getAssociatedDiseases() +// // also need ClinvarCache.getClinvarDataForGene(GeneIdentifier geneIdentifier) +// +// // Certain types of variants (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon +// // deletion) can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of tran- +// // scription or nonsense-mediated decay of an altered transcript. One must, however, exercise caution when classifying these +// // variants as pathogenic by considering the following principles: +// // (i) When classifying such variants as pathogenic, one must ensure that null variants are a known mechanism of +// // pathogenicity consistent with the established inheritance pattern for the disease. For example, there are genes for +// // which only heterozygous missense variants cause disease and null variants are benign in a heterozygous state (e.g., +// // many hypertrophic cardiomyopathy genes). A novel heterozygous nonsense variant in the MYH7 gene would +// // not be considered pathogenic for dominant hypertrophic cardiomyopathy based solely on this evidence, whereas a +// // novel heterozygous nonsense variant in the CFTR gene would likely be considered a recessive pathogenic variant. +// // Caveats: +// // • Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7) +// // • Use caution interpreting LOF variants at the extreme 3′ end of a gene +// // • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact +// // • Use caution in the presence of multiple transcripts +// +// GeneConstraint geneContraint = GeneConstraints.geneConstraint(variantEvaluation.getGeneSymbol()); +// // Should this be using the hasCompatibleDiseaseMatches variable? +// boolean inGeneWithKnownDiseaseAssociations = !knownDiseases.isEmpty(); +// if (inGeneWithKnownDiseaseAssociations && isLossOfFunctionEffect(variantEvaluation.getVariantEffect()) +// && (modeOfInheritance == ModeOfInheritance.ANY +// || compatibleWithRecessive(modeOfInheritance) +// || compatibleWithDominant(modeOfInheritance) && (geneContraint != null && geneContraint.isLossOfFunctionIntolerant()) +// ) +// ) { +// if (variantEvaluation.hasTranscriptAnnotations()) { +// TranscriptAnnotation transcriptAnnotation = variantEvaluation.getTranscriptAnnotations().get(0); +// if (predictedToLeadToNmd(transcriptAnnotation)) { +// acmgEvidenceBuilder.add(PVS1); +// } else { +// // Not predicted to lead to NMD? Downgrade to STRONG +// acmgEvidenceBuilder.add(PVS1, Evidence.STRONG); +// } +// } else { +// // shouldn't happen that there are no transcript annotations, but just in case... +// acmgEvidenceBuilder.add(PVS1, Evidence.STRONG); +// } +// } +// } +// +// private boolean isLossOfFunctionEffect(VariantEffect variantEffect) { +// return variantEffect == VariantEffect.START_LOST +// || variantEffect == VariantEffect.STOP_LOST +// || variantEffect == VariantEffect.STOP_GAINED +// || variantEffect == VariantEffect.FRAMESHIFT_ELONGATION +// || variantEffect == VariantEffect.FRAMESHIFT_TRUNCATION +// || variantEffect == VariantEffect.FRAMESHIFT_VARIANT +// || variantEffect == VariantEffect.SPLICE_ACCEPTOR_VARIANT +// || variantEffect == VariantEffect.SPLICE_DONOR_VARIANT +// || variantEffect == VariantEffect.EXON_LOSS_VARIANT; +// } +// +// private boolean predictedToLeadToNmd(TranscriptAnnotation transcriptAnnotation) { +// // predicted to lead to NMD if in last exon or last 50bp of penultimate exon, or in single exon transcript +// boolean notInLastExon = transcriptAnnotation.getRank() < transcriptAnnotation.getRankTotal(); +// boolean isSingleExonTranscript = transcriptAnnotation.getRankTotal() == 1; +// return transcriptAnnotation.getRankType() == TranscriptAnnotation.RankType.EXON && (notInLastExon || isSingleExonTranscript); +// } +// +// private boolean compatibleWithRecessive(ModeOfInheritance modeOfInheritance) { +// if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_RECESSIVE) { +// return true; +// } +// return probandSex == Individual.Sex.FEMALE && modeOfInheritance == ModeOfInheritance.X_RECESSIVE; +// } +// +// private boolean compatibleWithDominant(ModeOfInheritance modeOfInheritance) { +// if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_DOMINANT) { +// return true; +// } +// if (probandSex == Individual.Sex.MALE && (modeOfInheritance == ModeOfInheritance.X_RECESSIVE || modeOfInheritance == ModeOfInheritance.X_DOMINANT)) { +// return true; +// } +// return (probandSex == Individual.Sex.FEMALE || probandSex == Individual.Sex.UNKNOWN) && modeOfInheritance == ModeOfInheritance.X_DOMINANT; +// } /** * PM3 "For recessive disorders, detected in trans with a pathogenic variant" @@ -380,6 +385,8 @@ private void assignPM1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluati } } + // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" + // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" private void assignPS1PM5(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Map localClinVarData) { if (variantEvaluation.getTranscriptAnnotations().isEmpty()) { return; @@ -434,6 +441,10 @@ private boolean isMissenseOrInframeIndel(VariantEffect variantEffect) { * PP5 "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation" */ private void assignPP5(AcmgEvidence.Builder acmgEvidenceBuilder, ClinVarData clinVarData) { + // avoid double-counting by not assigning if PS1 already assigned + if (acmgEvidenceBuilder.contains(PS1)) { + return; + } ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); boolean pathOrLikelyPath = isPathOrLikelyPath(primaryInterpretation); if (pathOrLikelyPath && clinVarData.starRating() == 1) { @@ -662,8 +673,10 @@ private void assignPP4(AcmgEvidence.Builder acmgEvidenceBuilder, List diseaseModelPhenotypeMatch : compatibleDiseaseMatches) { humanGenePhenotypeScoreForMoi = Math.max(humanGenePhenotypeScoreForMoi, diseaseModelPhenotypeMatch.getScore()); } - if (humanGenePhenotypeScoreForMoi >= 0.6) { - acmgEvidenceBuilder.add(PP4); + if (humanGenePhenotypeScoreForMoi >= 0.7f) { + acmgEvidenceBuilder.add(PP4, Evidence.MODERATE); + } else if (humanGenePhenotypeScoreForMoi < 0.7f && humanGenePhenotypeScoreForMoi >= 0.51) { + acmgEvidenceBuilder.add(PP4, Evidence.SUPPORTING); } } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java index 46657d01d..4d41544fd 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java @@ -264,6 +264,10 @@ public boolean contains(AcmgCriterion acmgCriterion) { return evidence.containsKey(acmgCriterion); } + public boolean containsWithEvidence(AcmgCriterion acmgCriterion, Evidence evidenceStrength) { + return evidence.containsKey(acmgCriterion) && evidence.get(acmgCriterion) == evidenceStrength; + } + public AcmgEvidence build() { return evidence.isEmpty() ? EMPTY : new AcmgEvidence(evidence); } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java new file mode 100644 index 000000000..8a197862d --- /dev/null +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java @@ -0,0 +1,161 @@ +package org.monarchinitiative.exomiser.core.analysis.util.acmg; + +import de.charite.compbio.jannovar.annotation.VariantEffect; +import de.charite.compbio.jannovar.mendel.ModeOfInheritance; +import org.monarchinitiative.exomiser.core.analysis.util.GeneConstraint; +import org.monarchinitiative.exomiser.core.analysis.util.GeneConstraints; +import org.monarchinitiative.exomiser.core.model.Pedigree.Individual.Sex; +import org.monarchinitiative.exomiser.core.model.TranscriptAnnotation; +import org.monarchinitiative.exomiser.core.model.VariantEvaluation; +import org.monarchinitiative.exomiser.core.prioritisers.model.Disease; + +import java.util.List; + +import static org.monarchinitiative.exomiser.core.analysis.util.acmg.AcmgCriterion.PVS1; + +class AcmgPVS1EvidenceAssigner { + + private AcmgPVS1EvidenceAssigner() { + } + + /** + * Applies PVS1 according to guidelines in Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. + * + * PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" + */ + static void assignPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Sex probandSex, ModeOfInheritance + modeOfInheritance, List knownDiseases) { + // TODO: add new method - gene.getAssociatedDiseases() + // also need ClinvarCache.getClinvarDataForGene(GeneIdentifier geneIdentifier) + + // Certain types of variants (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon + // deletion) can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of tran- + // scription or nonsense-mediated decay of an altered transcript. One must, however, exercise caution when classifying these + // variants as pathogenic by considering the following principles: + // (i) When classifying such variants as pathogenic, one must ensure that null variants are a known mechanism of + // pathogenicity consistent with the established inheritance pattern for the disease. For example, there are genes for + // which only heterozygous missense variants cause disease and null variants are benign in a heterozygous state (e.g., + // many hypertrophic cardiomyopathy genes). A novel heterozygous nonsense variant in the MYH7 gene would + // not be considered pathogenic for dominant hypertrophic cardiomyopathy based solely on this evidence, whereas a + // novel heterozygous nonsense variant in the CFTR gene would likely be considered a recessive pathogenic variant. + // Caveats: + // • Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7) + // • Use caution interpreting LOF variants at the extreme 3′ end of a gene + // • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact + // • Use caution in the presence of multiple transcripts + + GeneConstraint geneConstraint = GeneConstraints.geneConstraint(variantEvaluation.getGeneSymbol()); + // Should this be using the hasCompatibleDiseaseMatches variable? + boolean inGeneWithKnownDiseaseAssociations = !knownDiseases.isEmpty(); + // TODO should modify the final strength according to ClinGen/GenCC known D2G validity - Table 1 of 10.1002/humu.23626 + VariantEffect variantEffect = variantEvaluation.getVariantEffect(); + if (inGeneWithKnownDiseaseAssociations && isLossOfFunctionEffect(variantEffect) + && (modeOfInheritance == ModeOfInheritance.ANY + || compatibleWithRecessive(probandSex, modeOfInheritance) + || compatibleWithDominant(probandSex, modeOfInheritance) && (geneConstraint != null && geneConstraint.isLossOfFunctionIntolerant()) + ) + ) { + switch (variantEffect) { + case STOP_LOST, STOP_GAINED, FRAMESHIFT_ELONGATION, FRAMESHIFT_TRUNCATION, FRAMESHIFT_VARIANT -> + assignNonsenseOrFrameshiftPVS1(acmgEvidenceBuilder, variantEvaluation); + case SPLICE_DONOR_VARIANT, SPLICE_ACCEPTOR_VARIANT -> + assignCanonicalSpliceDonorOrAcceptorPVS1(acmgEvidenceBuilder, variantEvaluation); + case TRANSCRIPT_ABLATION, EXON_LOSS_VARIANT -> + assignDeletionPVS1(acmgEvidenceBuilder, variantEvaluation); + case START_LOST -> assignInitiationCodonPVS1(acmgEvidenceBuilder, variantEvaluation); + default -> { // do not assign PVS1 + } + } + } + } + + private static void assignNonsenseOrFrameshiftPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation) { + if (predictedToLeadToNmd(variantEvaluation)) { + acmgEvidenceBuilder.add(PVS1); + } else { + acmgEvidenceBuilder.add(PVS1, AcmgCriterion.Evidence.STRONG); + } + } + + private static void assignCanonicalSpliceDonorOrAcceptorPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation) { + if (predictedToLeadToNmd(variantEvaluation)) { + acmgEvidenceBuilder.add(PVS1); + } else { + acmgEvidenceBuilder.add(PVS1, AcmgCriterion.Evidence.STRONG); + } + } + + private static void assignDeletionPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation) { + // full gene deletion -> PVS1 (Full gene deletion of haploinsufficient gene should be considered P (PVS1_StandAlone?) given absence of conflicting data) + VariantEffect variantEffect = variantEvaluation.getVariantEffect(); + if (variantEffect == VariantEffect.TRANSCRIPT_ABLATION || variantEffect == VariantEffect.EXON_LOSS_VARIANT && predictedToLeadToNmd(variantEvaluation)) { + // deletion of entire transcript + acmgEvidenceBuilder.add(PVS1); + } else { + acmgEvidenceBuilder.add(PVS1, AcmgCriterion.Evidence.STRONG); + } + } + + private static void assignInitiationCodonPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation) { + acmgEvidenceBuilder.add(PVS1, AcmgCriterion.Evidence.MODERATE); + } + + private static boolean isLossOfFunctionEffect(VariantEffect variantEffect) { + return isNonsenseOrFrameshift(variantEffect) + || isCanonicalSpliceDonorOrAcceptor(variantEffect) + || isGeneOrExonDeletion(variantEffect) + || isStartLost(variantEffect); + } + + private static boolean isNonsenseOrFrameshift(VariantEffect variantEffect) { + return variantEffect == VariantEffect.STOP_LOST + || variantEffect == VariantEffect.STOP_GAINED + || variantEffect == VariantEffect.FRAMESHIFT_ELONGATION + || variantEffect == VariantEffect.FRAMESHIFT_TRUNCATION + || variantEffect == VariantEffect.FRAMESHIFT_VARIANT; + } + + private static boolean isCanonicalSpliceDonorOrAcceptor(VariantEffect variantEffect) { + return variantEffect == VariantEffect.SPLICE_ACCEPTOR_VARIANT || variantEffect == VariantEffect.SPLICE_DONOR_VARIANT; + } + + private static boolean isGeneOrExonDeletion(VariantEffect variantEffect) { + return variantEffect == VariantEffect.EXON_LOSS_VARIANT || variantEffect == VariantEffect.TRANSCRIPT_ABLATION; + } + + private static boolean isStartLost(VariantEffect variantEffect) { + return variantEffect == VariantEffect.START_LOST; + } + + private static boolean predictedToLeadToNmd(VariantEvaluation variantEvaluation) { + if (variantEvaluation.hasTranscriptAnnotations()) { + TranscriptAnnotation transcriptAnnotation = variantEvaluation.getTranscriptAnnotations().get(0); + return predictedToLeadToNmd(transcriptAnnotation); + } + return false; + } + + private static boolean predictedToLeadToNmd(TranscriptAnnotation transcriptAnnotation) { + // predicted to lead to NMD if in last exon or last 50bp of penultimate exon, or in single exon transcript + boolean notInLastExon = transcriptAnnotation.getRank() < transcriptAnnotation.getRankTotal(); + boolean isSingleExonTranscript = transcriptAnnotation.getRankTotal() == 1; + return transcriptAnnotation.getRankType() == TranscriptAnnotation.RankType.EXON && (notInLastExon || isSingleExonTranscript); + } + + private static boolean compatibleWithRecessive(Sex probandSex, ModeOfInheritance modeOfInheritance) { + if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_RECESSIVE) { + return true; + } + return probandSex == Sex.FEMALE && modeOfInheritance == ModeOfInheritance.X_RECESSIVE; + } + + private static boolean compatibleWithDominant(Sex probandSex, ModeOfInheritance modeOfInheritance) { + if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_DOMINANT) { + return true; + } + if (probandSex == Sex.MALE && (modeOfInheritance == ModeOfInheritance.X_RECESSIVE || modeOfInheritance == ModeOfInheritance.X_DOMINANT)) { + return true; + } + return (probandSex == Sex.FEMALE || probandSex == Sex.UNKNOWN) && modeOfInheritance == ModeOfInheritance.X_DOMINANT; + } +} diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java new file mode 100644 index 000000000..26bd619d5 --- /dev/null +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java @@ -0,0 +1,212 @@ +package org.monarchinitiative.exomiser.core.analysis.util.acmg; + +import de.charite.compbio.jannovar.annotation.VariantEffect; +import de.charite.compbio.jannovar.mendel.ModeOfInheritance; +import org.monarchinitiative.exomiser.core.genome.dao.ClinVarDao; +import org.monarchinitiative.exomiser.core.model.VariantEvaluation; +import org.monarchinitiative.exomiser.core.model.pathogenicity.*; +import org.monarchinitiative.exomiser.core.prioritisers.model.Disease; +import org.monarchinitiative.svart.*; + +import java.util.*; +import java.util.regex.Matcher; +import java.util.regex.Pattern; + +import static de.charite.compbio.jannovar.annotation.VariantEffect.*; +import static org.monarchinitiative.exomiser.core.analysis.util.acmg.AcmgCriterion.*; + +class AcmgSpliceEvidenceAssigner { + + private AcmgSpliceEvidenceAssigner() { + } + + /** + * Applies PVS1, PS1, PP3, BP4, BP7 to splice region variants according to "Using the ACMG/AMP framework to capture + * evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup" + * https://doi.org/10.1016/j.ajhg.2023.06.002 + * @param acmgEvidenceBuilder + * @param variantEvaluation + * @param modeOfInheritance + * @param knownDiseases + * @param clinVarDao + */ + static void assignSpliceEvidence(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List knownDiseases, ClinVarDao clinVarDao) { + VariantEffect variantEffect = variantEvaluation.getVariantEffect(); + if (isSpliceDonorAcceptorSpliceVariant(variantEffect)) { + // PVS1 decision tree - this should have been independently added by the PVS1EvidenceAssigner class + // add PS1 modifier if PVS1 was assigned + assignDonorAcceptorPS1(acmgEvidenceBuilder, variantEvaluation, clinVarDao); + } else if (isNonDonorAcceptorSpliceRegionVariant(variantEffect)) { + // PP3+PS1 or BP4+BP7 + PathogenicityData pathogenicityData = variantEvaluation.getPathogenicityData(); + // The database only contains SpliceAI scores > 0.1. This means that any SNP with no score in the database can be considered as + // not impacting splicing. + PathogenicityScore spliceAiScore = pathogenicityData.pathogenicityScore(PathogenicitySource.SPLICE_AI); + if (variantEvaluation.variantType() == VariantType.SNV) { + float score = spliceAiScore == null ? 0 : spliceAiScore.getScore(); + assignSpliceAiBasedPP3Classification(acmgEvidenceBuilder, score); + if (acmgEvidenceBuilder.contains(PP3)) { + assignNonDonorAcceptorPS1(acmgEvidenceBuilder, variantEvaluation, clinVarDao); + } else if (acmgEvidenceBuilder.contains(BP4)) { + assignSilentIntronicBP7(acmgEvidenceBuilder, variantEvaluation); + } + } + } + } + + private static boolean assignSpliceAiBasedPP3Classification(AcmgEvidence.Builder acmgEvidenceBuilder, float spliceAiScore) { + // "Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup" + // DOI: 10.1016/j.ajhg.2023.06.002 + // variants outside of the +/-1,2 canonical splice acceptor/donor with a spliceAI: + // score >= 0.2 can be assigned PP3 + // score < 0.1 can be assigned BP4 + if (spliceAiScore >= 0.2) { + acmgEvidenceBuilder.add(PP3); + return true; + } else if (spliceAiScore < 0.1) { + acmgEvidenceBuilder.add(BP4); + return true; + } + return false; + } + + private static void assignNonDonorAcceptorPS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ClinVarDao clinVarDao) { + var localClinVarData = getClinVarDataSurroundingVariant(variantEvaluation, clinVarDao); + Set ps1Evidence = EnumSet.noneOf(AcmgCriterion.Evidence.class); + for (var entry : localClinVarData.entrySet()) { + GenomicVariant clinVarVariant = entry.getKey(); + ClinVarData clinVarData = entry.getValue(); + ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); + if (isNonDonorAcceptorSpliceRegionVariant(clinVarData.getVariantEffect()) && isPathOrLikelyPath(primaryInterpretation)) { + // same position in comparison to VUA + if (clinVarVariant.contains(variantEvaluation)) { + if (isPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.STRONG); + } else if (isLikelyPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.MODERATE); + } + } else { + // same splice region + if (isPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.MODERATE); + } else if (isLikelyPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.SUPPORTING); + } + } + } + } + addPs1Evidence(acmgEvidenceBuilder, ps1Evidence); + } + + private static final Pattern CDS_INTRONIC_HGVS = Pattern.compile("c\\.\\d+(?[+-])(?\\d+)[A-Z]+>[A-Z]+"); + private static final int DONOR_REGION_END = 6; + private static final int ACCEPTOR_REGION_START = 20; + private static void assignSilentIntronicBP7(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation) { + // (C) Silent (excluding last 3 nucleotides of exon and first nucleotide of exon) and intronic variants + // at or beyond the +7 and −21 positions (conservative designation for donor/acceptor splice region) or otherwise + // at or beyond the +7 and −4 positions (less conservative designation for the minimal donor/acceptor splice region). + + // currently we can't use the actual transcript to calculate the variant's position in the intron/exon, + // so we need to use the HGVS expression instead. + if (variantEvaluation.hasTranscriptAnnotations()) { + String hgvsc = variantEvaluation.getTranscriptAnnotations().get(0).getHgvsCdna(); + Matcher matcher = CDS_INTRONIC_HGVS.matcher(hgvsc); + if (matcher.matches()) { + String intronEnd = matcher.group("intronEnd"); + int position = Integer.parseInt(matcher.group("intronPos")); + if ("+".equals(intronEnd) && position > DONOR_REGION_END || "-".equals(intronEnd) && position > ACCEPTOR_REGION_START) { + acmgEvidenceBuilder.add(BP7); + } + } + } + } + + private static void assignDonorAcceptorPS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ClinVarDao clinVarDao) { + var localClinVarData = getClinVarDataSurroundingVariant(variantEvaluation, clinVarDao); + for (var entry : localClinVarData.entrySet()) { + ClinVarData clinVarData = entry.getValue(); + ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); + // Table 2. PS1 code weights for variants with same predicted splicing event as known (likely) pathogenic variant + VariantEffect clinVarVariantEffect = clinVarData.getVariantEffect(); + if (isSpliceVariant(clinVarVariantEffect) && isPathOrLikelyPath(primaryInterpretation)) { + Set ps1Evidence = EnumSet.noneOf(AcmgCriterion.Evidence.class); + if (acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.VERY_STRONG)) { + // same position in comparison to VUA + if (isSpliceDonorAcceptorSpliceVariant(clinVarVariantEffect) && isPath(primaryInterpretation) || + isNonDonorAcceptorSpliceRegionVariant(clinVarVariantEffect) && isLikelyPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.SUPPORTING); + } + } + else if (acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.STRONG) + || acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.MODERATE) + || acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.SUPPORTING)) { + // same splice region as VUA + if (isSpliceDonorAcceptorSpliceVariant(clinVarVariantEffect) && isPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.STRONG); + } else if (isNonDonorAcceptorSpliceRegionVariant(clinVarVariantEffect) && isPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.MODERATE); + } else if (isNonDonorAcceptorSpliceRegionVariant(clinVarVariantEffect) && isLikelyPath(primaryInterpretation)) { + ps1Evidence.add(Evidence.SUPPORTING ); + } + } + addPs1Evidence(acmgEvidenceBuilder, ps1Evidence); + } + } + } + + private static Map getClinVarDataSurroundingVariant(VariantEvaluation variantEvaluation, ClinVarDao clinVarDao) { + // ensure region is within contig bounds + Contig contig = variantEvaluation.contig(); + var upStream = Math.max(1, variantEvaluation.start() - 25); + var downStream = Math.min(contig.length(), variantEvaluation.start() + 25); + GenomicInterval genomicInterval = GenomicInterval.of(contig, Strand.POSITIVE, Coordinates.oneBased(upStream, downStream)); + return clinVarDao.findClinVarRecordsOverlappingInterval(genomicInterval); + } + + private static boolean isPath(ClinVarData.ClinSig clinSig) { + return clinSig == ClinVarData.ClinSig.PATHOGENIC; + } + + private static boolean isLikelyPath(ClinVarData.ClinSig clinSig) { + return clinSig == ClinVarData.ClinSig.LIKELY_PATHOGENIC || clinSig == ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC; + } + + private static boolean isPathOrLikelyPath(ClinVarData.ClinSig clinSig) { + return clinSig == ClinVarData.ClinSig.PATHOGENIC || clinSig == ClinVarData.ClinSig.LIKELY_PATHOGENIC || clinSig == ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC; + } + + /** + * Returns true if the variantEffect is a SPLICE_REGION, SPLICE_DONOR or SPLICE_ACCEPTOR type. + * + * @param variantEffect + * @return + */ + private static boolean isSpliceVariant(VariantEffect variantEffect) { + return isSpliceDonorAcceptorSpliceVariant(variantEffect) || isNonDonorAcceptorSpliceRegionVariant(variantEffect); + } + + private static boolean isNonDonorAcceptorSpliceRegionVariant(VariantEffect variantEffect) { + return variantEffect == SPLICE_REGION_VARIANT; + } + + private static boolean isSpliceDonorAcceptorSpliceVariant(VariantEffect variantEffect) { + return variantEffect == SPLICE_DONOR_VARIANT || variantEffect == SPLICE_ACCEPTOR_VARIANT; + } + + private static void addPs1Evidence(AcmgEvidence.Builder acmgEvidenceBuilder, Set ps1Evidence) { + for (Evidence evidence : ps1Evidence) { + switch (evidence) { + case STRONG: + acmgEvidenceBuilder.add(PS1); + break; + case MODERATE: + acmgEvidenceBuilder.add(PS1, Evidence.MODERATE); + break; + case SUPPORTING: + acmgEvidenceBuilder.add(PS1, Evidence.SUPPORTING); + break; + } + } + } + +} diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java index 32e925266..157c13531 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java @@ -156,11 +156,10 @@ public PathogenicityData getVariantPathogenicityData(Variant variant, SetJaganathan et al, Cell 2019) max delta score. + * This is the max score from the DL/DG/AL/AG scores >= minScore. The min score for this was set to 0.2, so scores lower + * than this will likely not be present in the database, unless guidance changes later. + *
+ * Delta score of a variant, defined as the maximum of (DS_AG, DS_AL, DS_DG, DS_DL), ranges from 0 to 1 and can be interpreted as the probability of the variant being splice-altering. In the paper, a detailed characterization is provided for 0.2 (high recall), 0.5 (recommended), and 0.8 (high precision) cutoffs. Delta position conveys information about the location where splicing changes relative to the variant position (positive values are downstream of the variant, negative values are upstream). + *
+ * + * These annotations are free for academic and not-for-profit use; other use requires a commercial license from Illumina, Inc. + * + * https://github.com/Illumina/SpliceAI + **/ public class SpliceAiScore extends BasePathogenicityScore { + public static float NON_SPLICEOGENIC_SCORE = 0.1f; + public static float PERMISSIVE_SPLICEOGENIC_SCORE = 0.2f; + public static float DEFAULT_SPLICEOGENIC_SCORE = 0.5f; + public static float HIGH_CONFIDENCE_SPLICEOGENIC_SCORE = 0.8f; + public static SpliceAiScore of(float score) { return new SpliceAiScore(score); } diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java index 79f5d7853..5fae61294 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java @@ -545,8 +545,12 @@ public void testRevelOverridesAllOtherScores(float revelScore, AcmgCriterion acm } // PP4 - @Test - void testAssignsPP4() { + @ParameterizedTest + @CsvSource({ + "0.51, SUPPORTING", + "0.7, MODERATE", + }) + void testAssignsPP4(float phenotypeScore, Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") .geneSymbol("PTEN") @@ -555,10 +559,11 @@ void testAssignsPP4() { .build(); Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); // High phenotype match triggers - PP4 - List> compatibleDiseaseMatches = List.of(ModelPhenotypeMatch.of(0.6, cowdenSyndrome, List.of())); + List> compatibleDiseaseMatches = List.of(ModelPhenotypeMatch.of(phenotypeScore, cowdenSyndrome, List.of())); AcmgEvidence acmgEvidence = instance.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(variantEvaluation), List.of(cowdenSyndrome), compatibleDiseaseMatches); - assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(AcmgCriterion.PP4).build())); + AcmgEvidence expected = evidence == null ? AcmgEvidence.empty() : AcmgEvidence.builder().add(PP4, evidence).build(); + assertThat(acmgEvidence, equalTo(expected)); } @Nested diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java index f2568b849..6a430a63d 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java @@ -115,6 +115,15 @@ public void testBuilderContainsEvidence() { assertThat(instance.contains(PM3), equalTo(false)); } + @Test + public void testBuilderContainsEvidenceWithStrength() { + AcmgEvidence.Builder instance = AcmgEvidence.builder() + .add(PVS1, Evidence.MODERATE); + assertThat(instance.containsWithEvidence(PVS1, Evidence.MODERATE), equalTo(true)); + assertThat(instance.containsWithEvidence(PVS1, Evidence.VERY_STRONG), equalTo(false)); + assertThat(instance.containsWithEvidence(PM3, Evidence.MODERATE), equalTo(false)); + } + @Test public void testSizeWhenEmpty() { AcmgEvidence instance = AcmgEvidence.builder().build(); diff --git a/exomiser-web/src/main/java/org/monarchinitiative/exomiser/web/controller/SubmitJobController.java b/exomiser-web/src/main/java/org/monarchinitiative/exomiser/web/controller/SubmitJobController.java index c43e0ce86..b4e1912f9 100644 --- a/exomiser-web/src/main/java/org/monarchinitiative/exomiser/web/controller/SubmitJobController.java +++ b/exomiser-web/src/main/java/org/monarchinitiative/exomiser/web/controller/SubmitJobController.java @@ -79,8 +79,6 @@ public class SubmitJobController { VariantEffect.DOWNSTREAM_GENE_VARIANT, VariantEffect.CODING_TRANSCRIPT_INTRON_VARIANT, VariantEffect.NON_CODING_TRANSCRIPT_INTRON_VARIANT, - VariantEffect.SYNONYMOUS_VARIANT, - VariantEffect.SPLICE_REGION_VARIANT, VariantEffect.REGULATORY_REGION_VARIANT ); From 4a6176508180db9cc8c4993bbb81878bc27f89d9 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Mon, 10 Jun 2024 14:59:58 +0100 Subject: [PATCH 04/21] Fix for issue #560 Update ClinVarAlleleParser to handle new risk allele annotations. Add new risk allele categories to allele.proto, ClinVarData and AlleleProtoAdaptor and AlleleConverter --- .../core/model/AlleleProtoAdaptor.java | 3 + .../core/model/pathogenicity/ClinVarData.java | 22 +- exomiser-core/src/main/proto/allele.proto | 5 + .../data/genome/indexers/AlleleConverter.java | 3 + .../model/parsers/ClinVarAlleleParser.java | 94 +++++-- .../model/parsers/DbSnpAlleleParser.java | 1 - .../genome/indexers/AlleleConverterTest.java | 4 + .../parsers/ClinVarAlleleParserTest.java | 251 ++++++++++++++++-- 8 files changed, 336 insertions(+), 47 deletions(-) diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java index d9e12d579..05bec17c1 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java @@ -301,6 +301,9 @@ private static ClinVarData.ClinSig toClinSig(ClinVar.ClinSig protoClinSig) { case OTHER -> ClinVarData.ClinSig.OTHER; case PROTECTIVE -> ClinVarData.ClinSig.PROTECTIVE; case RISK_FACTOR -> ClinVarData.ClinSig.RISK_FACTOR; + case UNCERTAIN_RISK_ALLELE -> ClinVarData.ClinSig.UNCERTAIN_RISK_ALLELE; + case LIKELY_RISK_ALLELE -> ClinVarData.ClinSig.LIKELY_RISK_ALLELE; + case ESTABLISHED_RISK_ALLELE -> ClinVarData.ClinSig.ESTABLISHED_RISK_ALLELE; case NOT_PROVIDED, UNRECOGNIZED -> ClinVarData.ClinSig.NOT_PROVIDED; }; } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/pathogenicity/ClinVarData.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/pathogenicity/ClinVarData.java index d597fb17d..4719c550f 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/pathogenicity/ClinVarData.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/pathogenicity/ClinVarData.java @@ -37,6 +37,10 @@ public class ClinVarData { private static final ClinVarData EMPTY = new Builder().build(); + /** + * Based on the categories from the ClinVar docs and + * what actually shows up in the VCF file. + */ public enum ClinSig { // ACMG/AMP-based PATHOGENIC, @@ -47,6 +51,11 @@ public enum ClinSig { BENIGN_OR_LIKELY_BENIGN, BENIGN, CONFLICTING_PATHOGENICITY_INTERPRETATIONS, + // As recommended by ClinGen (https://pubmed.ncbi.nlm.nih.gov/38054408/) for variants with decreased penetrance + // for Mendelian diseases. + UNCERTAIN_RISK_ALLELE, + LIKELY_RISK_ALLELE, + ESTABLISHED_RISK_ALLELE, //Non-ACMG-based AFFECTS, ASSOCIATION, @@ -83,11 +92,16 @@ public int starRating() { public static ReviewStatus parseReviewStatus(String reviewStatus) { return switch (reviewStatus.replace("_", " ")) { - case "no assertion criteria provided" -> NO_ASSERTION_CRITERIA_PROVIDED; - case "no interpretation for the single variant", "no interpretation for the individual variant" -> - NO_INTERPRETATION_FOR_THE_SINGLE_VARIANT; + case "no assertion provided", + "no assertion criteria provided", + "no classification provided", + "no classifications from unflagged records" -> NO_ASSERTION_CRITERIA_PROVIDED; + case "no interpretation for the single variant", + "no interpretation for the individual variant", + "no classification for the single variant"-> NO_INTERPRETATION_FOR_THE_SINGLE_VARIANT; case "criteria provided, single submitter" -> CRITERIA_PROVIDED_SINGLE_SUBMITTER; - case "criteria provided, conflicting interpretations" -> CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS; + case "criteria provided, conflicting interpretations", + "criteria provided, conflicting classifications" -> CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS; case "criteria provided, multiple submitters, no conflicts" -> CRITERIA_PROVIDED_MULTIPLE_SUBMITTERS_NO_CONFLICTS; case "reviewed by expert panel" -> REVIEWED_BY_EXPERT_PANEL; diff --git a/exomiser-core/src/main/proto/allele.proto b/exomiser-core/src/main/proto/allele.proto index 9a06eabf8..b60781860 100644 --- a/exomiser-core/src/main/proto/allele.proto +++ b/exomiser-core/src/main/proto/allele.proto @@ -161,6 +161,11 @@ message ClinVar { OTHER = 12; PROTECTIVE = 13; RISK_FACTOR = 14; + // As recommended by ClinGen (https://pubmed.ncbi.nlm.nih.gov/38054408/) for variants with decreased penetrance + // for Mendelian diseases. + UNCERTAIN_RISK_ALLELE = 15; + LIKELY_RISK_ALLELE = 16; + ESTABLISHED_RISK_ALLELE = 17; } enum ReviewStatus { diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverter.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverter.java index eafdce07c..25d785932 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverter.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverter.java @@ -172,6 +172,9 @@ private static ClinVar.ClinSig toProtoClinSig(ClinVarData.ClinSig clinSig) { case PATHOGENIC_OR_LIKELY_PATHOGENIC -> ClinVar.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC; case PATHOGENIC -> ClinVar.ClinSig.PATHOGENIC; case CONFLICTING_PATHOGENICITY_INTERPRETATIONS -> ClinVar.ClinSig.CONFLICTING_PATHOGENICITY_INTERPRETATIONS; + case UNCERTAIN_RISK_ALLELE -> ClinVar.ClinSig.UNCERTAIN_RISK_ALLELE; + case LIKELY_RISK_ALLELE -> ClinVar.ClinSig.LIKELY_RISK_ALLELE; + case ESTABLISHED_RISK_ALLELE -> ClinVar.ClinSig.ESTABLISHED_RISK_ALLELE; case AFFECTS -> ClinVar.ClinSig.AFFECTS; case ASSOCIATION -> ClinVar.ClinSig.ASSOCIATION; case DRUG_RESPONSE -> ClinVar.ClinSig.DRUG_RESPONSE; diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParser.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParser.java index 5126a6f61..1732c027f 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParser.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParser.java @@ -28,6 +28,7 @@ import org.slf4j.LoggerFactory; import java.util.*; +import java.util.stream.Collectors; import static org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData.ClinSig.*; @@ -38,6 +39,47 @@ public class ClinVarAlleleParser extends VcfAlleleParser { private static final Logger logger = LoggerFactory.getLogger(ClinVarAlleleParser.class); + private static final Map CLINSIG_MAP; + + static { + Map temp = new HashMap<>(); + temp.put("Uncertain_significance", UNCERTAIN_SIGNIFICANCE); +// temp.put("Uncertain_significance/Uncertain_risk_allele", UNCERTAIN_SIGNIFICANCE); + temp.put("Benign", BENIGN); +// temp.put("Benign/Likely_benign", BENIGN_OR_LIKELY_BENIGN); + temp.put("Likely_benign", LIKELY_BENIGN); + temp.put("Conflicting_interpretations_of_pathogenicity", CONFLICTING_PATHOGENICITY_INTERPRETATIONS); + temp.put("Conflicting_classifications_of_pathogenicity", CONFLICTING_PATHOGENICITY_INTERPRETATIONS); + temp.put("Likely_pathogenic", LIKELY_PATHOGENIC); + temp.put("Likely_pathogenic,_low_penetrance", LIKELY_PATHOGENIC); + temp.put("Likely_pathogenic/Likely_risk_allele", LIKELY_PATHOGENIC); + temp.put("Likely_pathogenic/Established_risk_allele", LIKELY_PATHOGENIC); + temp.put("Pathogenic/Likely_pathogenic", PATHOGENIC_OR_LIKELY_PATHOGENIC); + temp.put("Pathogenic/Likely_pathogenic/Likely_risk_allele", PATHOGENIC_OR_LIKELY_PATHOGENIC); + temp.put("Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance", PATHOGENIC_OR_LIKELY_PATHOGENIC); + temp.put("Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance/Established_risk_allele" + , PATHOGENIC_OR_LIKELY_PATHOGENIC); + temp.put("Pathogenic", PATHOGENIC); + temp.put("Pathogenic,_low_penetrance", PATHOGENIC); + temp.put("Pathogenic/Likely_risk_allele", PATHOGENIC); + temp.put("Pathogenic/Pathogenic,_low_penetrance", PATHOGENIC); + temp.put("Uncertain_risk_allele", UNCERTAIN_RISK_ALLELE); + temp.put("Likely_risk_allele", LIKELY_RISK_ALLELE); + temp.put("Established_risk_allele", ESTABLISHED_RISK_ALLELE); + temp.put("not_provided", NOT_PROVIDED); + temp.put("no_classification_for_the_single_variant", NOT_PROVIDED); + temp.put("no_classifications_from_unflagged_records", NOT_PROVIDED); + temp.put("Affects", AFFECTS); + temp.put("association", ASSOCIATION); + temp.put("association_not_found", ASSOCIATION); // TODO add ASSOCIATION_NOT_FOUND + temp.put("drug_response", DRUG_RESPONSE); + temp.put("other", OTHER); + temp.put("confers_sensitivity", OTHER); + temp.put("protective", PROTECTIVE); + temp.put("risk_factor", RISK_FACTOR); + CLINSIG_MAP = Map.copyOf(temp); + } + @Override List parseInfoField(List alleles, String info) { for (Allele allele : alleles) { @@ -68,11 +110,9 @@ private ClinVarData parseClinVarData(Allele allele, String info) { String value = keyValue[1]; switch (key) { case "CLNSIG": - String[] clinsigs = value.split(",_"); - ClinSig primary = parseClinSig(clinsigs[0]); - Set secondary = parseSecondaryClinSig(clinsigs); - clinVarBuilder.primaryInterpretation(primary); - clinVarBuilder.secondaryInterpretations(secondary); + String[] clinsigs = value.split("\\|"); + clinVarBuilder.primaryInterpretation(parseClinSig(clinsigs[0])); + clinVarBuilder.secondaryInterpretations(parseSecondaryClinSig(clinsigs)); break; case "CLNREVSTAT": //CLNREVSTAT criteria_provided,_conflicting_interpretations, criteria_provided,_multiple_submitters,_no_conflicts, criteria_provided,_single_submitter, no_assertion_criteria_provided, no_assertion_provided, no_interpretation_for_the_single_variant, practice_guideline, reviewed_by_expert_panel @@ -143,23 +183,33 @@ private ClinSig parseClinSig(String clinsig) { // Likely_benign=52064, Likely_pathogenic=15127, Pathogenic=46803, Pathogenic/Likely_pathogenic=3278, // Uncertain_significance=120418, association=148, drug_response=290, not_provided=10980, other=1796, protective=30, // risk_factor=411 - return switch (clinsig) { - case "Uncertain_significance" -> UNCERTAIN_SIGNIFICANCE; - case "Benign" -> BENIGN; - case "Benign/Likely_benign" -> BENIGN_OR_LIKELY_BENIGN; - case "Likely_benign" -> LIKELY_BENIGN; - case "Conflicting_interpretations_of_pathogenicity" -> CONFLICTING_PATHOGENICITY_INTERPRETATIONS; - case "Likely_pathogenic" -> LIKELY_PATHOGENIC; - case "Pathogenic/Likely_pathogenic" -> PATHOGENIC_OR_LIKELY_PATHOGENIC; - case "Pathogenic" -> PATHOGENIC; - case "Affects" -> AFFECTS; - case "association" -> ASSOCIATION; - case "drug_response" -> DRUG_RESPONSE; - case "other" -> OTHER; - case "protective" -> PROTECTIVE; - case "risk_factor" -> RISK_FACTOR; - default -> NOT_PROVIDED; - }; + + // this is yuk! + clinsig = clinsig.replace(",_low_penetrance", ""); + Set clinSigs = Arrays.stream(clinsig.split("/")) + .map(CLINSIG_MAP::get) + .collect(Collectors.toCollection(() -> EnumSet.noneOf(ClinSig.class))); + + if (clinSigs.isEmpty()) { + throw new IllegalArgumentException("'" + clinsig + "' is not a recognised ClinVar CLNSIG value"); + } + if (clinSigs.size() == 1) { + return clinSigs.iterator().next(); + } + // remove the risk allele if present and try to figure out if it's a P/LP or B/LB + clinSigs.removeAll(EnumSet.of(UNCERTAIN_RISK_ALLELE, LIKELY_RISK_ALLELE, ESTABLISHED_RISK_ALLELE)); + + if (clinSigs.size() == 1) { + return clinSigs.iterator().next(); + } + else if (clinSigs.contains(PATHOGENIC) && clinSigs.contains(LIKELY_PATHOGENIC)) { + return PATHOGENIC_OR_LIKELY_PATHOGENIC; + } + else if (clinSigs.contains(BENIGN) && clinSigs.contains(LIKELY_BENIGN)) { + return BENIGN_OR_LIKELY_BENIGN; + } + // shouldn't get here.... + throw new IllegalArgumentException("'" + clinsig + "' is not a recognised ClinVar CLNSIG value"); } } diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/DbSnpAlleleParser.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/DbSnpAlleleParser.java index 15a623387..95676cdba 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/DbSnpAlleleParser.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/model/parsers/DbSnpAlleleParser.java @@ -41,7 +41,6 @@ public class DbSnpAlleleParser extends VcfAlleleParser { @Override List parseInfoField(List alleles, String info) { - System.out.println(info); Map> minorAlleleFrequencies = parseMinorAlleleFrequencies(info); for (Map.Entry> entry : minorAlleleFrequencies.entrySet()) { diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverterTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverterTest.java index 30b9281d9..d6357748b 100644 --- a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverterTest.java +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/indexers/AlleleConverterTest.java @@ -199,10 +199,14 @@ public void convertClinVar() { @Test public void convertClinVarConflictingInterpretationCounts() { ClinVarData clinVarData = ClinVarData.builder() + .primaryInterpretation(ClinVarData.ClinSig.CONFLICTING_PATHOGENICITY_INTERPRETATIONS) + .reviewStatus(ClinVarData.ReviewStatus.CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) .conflictingInterpretationCounts(Map.of(ClinVarData.ClinSig.PATHOGENIC, 3, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE, 2)) .build(); ClinVar expected = ClinVar.newBuilder() + .setPrimaryInterpretation(ClinVar.ClinSig.CONFLICTING_PATHOGENICITY_INTERPRETATIONS) + .setReviewStatus(ClinVar.ReviewStatus.CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) .putAllClinSigCounts(Map.of("PATHOGENIC", 3, "UNCERTAIN_SIGNIFICANCE", 2)) .build(); diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java index c19fbe9cd..b24cccfc3 100644 --- a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java @@ -20,13 +20,25 @@ package org.monarchinitiative.exomiser.data.genome.model.parsers; +import org.junit.jupiter.api.Disabled; import org.junit.jupiter.api.Test; +import org.monarchinitiative.exomiser.core.model.AlleleProtoAdaptor; import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData; +import org.monarchinitiative.exomiser.core.proto.AlleleProto; +import org.monarchinitiative.exomiser.data.genome.indexers.AlleleConverter; import org.monarchinitiative.exomiser.data.genome.model.Allele; -import java.util.EnumSet; -import java.util.List; -import java.util.Map; +import java.io.*; +import java.nio.file.Files; +import java.nio.file.Path; +import java.util.*; +import java.util.function.Function; +import java.util.stream.Collectors; +import java.util.stream.Stream; +import java.util.zip.GZIPInputStream; + +import static org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData.ClinSig.*; +import static org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData.ReviewStatus.*; /** @@ -86,8 +98,8 @@ public void testParseClnSigPathogenic() { expected.setRsId("7105"); expected.setClinVarData(ClinVarData.builder() .variationId("7105") - .primaryInterpretation(ClinVarData.ClinSig.PATHOGENIC) - .reviewStatus(ClinVarData.ReviewStatus.PRACTICE_GUIDELINE) + .primaryInterpretation(PATHOGENIC) + .reviewStatus(PRACTICE_GUIDELINE) .build()); assertParseLineEquals(line, List.of(expected)); @@ -100,8 +112,8 @@ public void testParseClnSigLikelyPathogenic() { expected.setRsId("121918506"); expected.setClinVarData(ClinVarData.builder() .variationId("374823") - .primaryInterpretation(ClinVarData.ClinSig.LIKELY_PATHOGENIC) - .reviewStatus(ClinVarData.ReviewStatus.CRITERIA_PROVIDED_SINGLE_SUBMITTER) + .primaryInterpretation(LIKELY_PATHOGENIC) + .reviewStatus(CRITERIA_PROVIDED_SINGLE_SUBMITTER) .build()); assertParseLineEquals(line, List.of(expected)); @@ -112,7 +124,7 @@ public void testParseClnSig() { String line = "1 28590 . T TTGG 999 PASS ALLELEID=12345;CLNSIG=Benign/Likely_benign"; Allele expected = new Allele(1, 28590, "T", "TTGG"); expected.setClinVarData(ClinVarData.builder() - .primaryInterpretation(ClinVarData.ClinSig.BENIGN_OR_LIKELY_BENIGN) + .primaryInterpretation(BENIGN_OR_LIKELY_BENIGN) .build()); assertParseLineEquals(line, List.of(expected)); @@ -120,11 +132,13 @@ public void testParseClnSig() { @Test public void testParseClnSigWithSecondary() { - String line = "1 28590 . T TTGG 999 PASS ALLELEID=12345;CLNSIG=Pathogenic/Likely_pathogenic,_other,_association"; + // as of approx. Feb 2024 ClinVar changed their delimiters from ',_' to '|' so the parser will now only recognise + // files released after this date. + String line = "1 28590 . T TTGG 999 PASS ALLELEID=12345;CLNSIG=Pathogenic/Likely_pathogenic|other|association"; Allele expected = new Allele(1, 28590, "T", "TTGG"); expected.setClinVarData(ClinVarData.builder() - .primaryInterpretation(ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC) - .secondaryInterpretations(EnumSet.of(ClinVarData.ClinSig.OTHER, ClinVarData.ClinSig.ASSOCIATION)) + .primaryInterpretation(PATHOGENIC_OR_LIKELY_PATHOGENIC) + .secondaryInterpretations(EnumSet.of(OTHER, ASSOCIATION)) .build()); assertParseLineEquals(line, List.of(expected)); @@ -144,7 +158,7 @@ public void testParseClnRevStat() { String line = "1 28590 . T TTGG 999 PASS ALLELEID=12345;CLNREVSTAT=criteria_provided,_conflicting_interpretations"; Allele expected = new Allele(1, 28590, "T", "TTGG"); expected.setClinVarData(ClinVarData.builder() - .reviewStatus(ClinVarData.ReviewStatus.CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) + .reviewStatus(CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) .build()); assertParseLineEquals(line, List.of(expected)); @@ -155,7 +169,7 @@ public void testParseClinSigIncl() { String line = "1 28590 . T TTGG 999 PASS ALLELEID=12345;CLNSIGINCL=424752:Pathogenic"; Allele expected = new Allele(1, 28590, "T", "TTGG"); expected.setClinVarData(ClinVarData.builder() - .includedAlleles(Map.of("424752", ClinVarData.ClinSig.PATHOGENIC)) + .includedAlleles(Map.of("424752", PATHOGENIC)) .build()); assertParseLineEquals(line, List.of(expected)); @@ -167,8 +181,8 @@ public void testParseClinSigInclMulti() { Allele expected = new Allele(1, 28590, "T", "TTGG"); expected.setClinVarData(ClinVarData.builder() .includedAlleles(Map.of( - "424752", ClinVarData.ClinSig.PATHOGENIC, - "15612", ClinVarData.ClinSig.OTHER + "424752", PATHOGENIC, + "15612", OTHER )) .build()); @@ -182,9 +196,9 @@ public void testParseClinSigNoNumbers() { expected.setRsId("25511"); expected.setClinVarData(ClinVarData.builder() .variationId("25511") - .reviewStatus(ClinVarData.ReviewStatus.NO_INTERPRETATION_FOR_THE_SINGLE_VARIANT) + .reviewStatus(NO_INTERPRETATION_FOR_THE_SINGLE_VARIANT) .includedAlleles(Map.of( - "8152", ClinVarData.ClinSig.PATHOGENIC + "8152", PATHOGENIC )) .build()); @@ -198,15 +212,64 @@ void testParseClinSigConf() { expected.setRsId("369982920"); expected.setClinVarData(ClinVarData.builder() .variationId("218256") - .primaryInterpretation(ClinVarData.ClinSig.CONFLICTING_PATHOGENICITY_INTERPRETATIONS) - .reviewStatus(ClinVarData.ReviewStatus.CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) + .primaryInterpretation(CONFLICTING_PATHOGENICITY_INTERPRETATIONS) + .reviewStatus(CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) + // CLNSIGCONF=Pathogenic(5)|Uncertain_significance(1) + .conflictingInterpretationCounts(Map.of(PATHOGENIC, 5, UNCERTAIN_SIGNIFICANCE, 1)) + .build()); + + assertParseLineEquals(line, List.of(expected)); + } + + /** + * Test for issue 560 + */ + @Test + void testParseClinSigConfClassification() { + String line = "11\t47352652\t506638\tA\tG\t.\t.\tALLELEID=503825;CLNDISDB=MedGen:CN230736|MedGen:CN169374;CLNDN=Cardiovascular_phenotype|not_specified;CLNHGVS=NC_000011.10:g.47352652A>G;CLNREVSTAT=criteria_provided,_conflicting_classifications;CLNSIG=Conflicting_classifications_of_pathogenicity;CLNSIGCONF=Uncertain_significance(1)|Likely_benign(1);CLNVC=single_nucleotide_variant;CLNVCSO=SO:0001483;CLNVI=ClinGen:CA658797649;GENEINFO=MYBPC3:4607;ORIGIN=1;RS=886048383"; + Allele expected = new Allele(11, 47352652, "A", "G"); + expected.setRsId("886048383"); + expected.setClinVarData(ClinVarData.builder() + .variationId("506638") + .primaryInterpretation(CONFLICTING_PATHOGENICITY_INTERPRETATIONS) + .reviewStatus(CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) // CLNSIGCONF=Pathogenic(5)|Uncertain_significance(1) - .conflictingInterpretationCounts(Map.of(ClinVarData.ClinSig.PATHOGENIC, 5, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE, 1)) + .conflictingInterpretationCounts(Map.of(UNCERTAIN_SIGNIFICANCE, 1, LIKELY_BENIGN, 1)) .build()); + assertParseLineEquals(line, List.of(expected)); + } + @Test + void unrecognisedClinSigCombo() { + String line = "X\t153763492\t100055\tT\tC\t.\t.\tAF_TGP=0.09457;ALLELEID=25399;CLNDISDB=MONDO:MONDO:0005775,MedGen:C2939465|MONDO:MONDO:0010480,MedGen:C2720289,OMIM:300908,Orphanet:466026|MeSH:D030342,MedGen:C0950123|MedGen:C3661900|MedGen:CN169374|.|MONDO:MONDO:0021024,MedGen:C1970028,OMIM:611162,Orphanet:673|MedGen:C3806712,OMIM:300910,Orphanet:391330;CLNDN=G6PD_deficiency|Anemia,_nonspherocytic_hemolytic,_due_to_G6PD_deficiency|Inborn_genetic_diseases|not_provided|not_specified|G6PD_A+|Malaria,_susceptibility_to|Bone_mineral_density_quantitative_trait_locus_18;CLNHGVS=NC_000023.10:g.153763492T>C;CLNREVSTAT=criteria_provided,_conflicting_classifications;CLNSIG=Conflicting_classifications_of_pathogenicity;CLNSIGCONF=Pathogenic(10)|Likely_pathogenic(1)|Uncertain_significance(5)|Benign(1)|Likely_benign(3);CLNVC=single_nucleotide_variant;CLNVCSO=SO:0001483;CLNVI=ClinGen:CA120939|Genetic_Testing_Registry_(GTR):GTR000167633|OMIM:305900.0001|OMIM:305900.0002|OMIM:305900.0023;GENEINFO=G6PD:2539;MC=SO:0001583|missense_variant;ORIGIN=17;RS=1050829;CLNDISDBINCL=MONDO:MONDO:0010480,MedGen:C2720289,OMIM:300908,Orphanet:466026|.|MONDO:MONDO:0005775,MedGen:C2939465;CLNDNINCL=Anemia,_nonspherocytic_hemolytic,_due_to_G6PD_deficiency|G6PD_SANTAMARIA|G6PD_deficiency;CLNSIGINCL=10361:Likely_pathogenic/Established_risk_allele|10382:Likely_pathogenic|1065168:Pathogenic|1722597:Likely_pathogenic|1722617:Likely_pathogenic|1722622:Likely_pathogenic|1722693:Uncertain_significance|1722697:Uncertain_significance|1722698:Uncertain_significance|1722726:Likely_pathogenic|1722747:Likely_pathogenic"; + Allele expected = new Allele(23, 153763492, "T", "C"); + expected.setRsId("1050829"); + Map includedAlleles = new HashMap<>(); + includedAlleles.put("1722747", LIKELY_PATHOGENIC); + includedAlleles.put("1722726", LIKELY_PATHOGENIC); + includedAlleles.put("1722617", LIKELY_PATHOGENIC); + includedAlleles.put("1722622", LIKELY_PATHOGENIC); + includedAlleles.put("10361", LIKELY_PATHOGENIC); // CLNSIGINCL=10361:Likely_pathogenic/Established_risk_allele + includedAlleles.put("10382", LIKELY_PATHOGENIC); + includedAlleles.put("1722597", LIKELY_PATHOGENIC); + includedAlleles.put("1722697", UNCERTAIN_SIGNIFICANCE); + includedAlleles.put("1722698", UNCERTAIN_SIGNIFICANCE); + includedAlleles.put("1065168", PATHOGENIC); + includedAlleles.put("1722693", UNCERTAIN_SIGNIFICANCE); + expected.setClinVarData(ClinVarData.builder() + .variationId("100055") + .primaryInterpretation(CONFLICTING_PATHOGENICITY_INTERPRETATIONS) + .reviewStatus(CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) + .conflictingInterpretationCounts(Map.of(PATHOGENIC, 10, LIKELY_PATHOGENIC, 1, UNCERTAIN_SIGNIFICANCE, 5, LIKELY_BENIGN, 3, BENIGN, 1)) + .includedAlleles(includedAlleles) + .build()); assertParseLineEquals(line, List.of(expected)); } + + // 4 6301479 215392 G C . . ALLELEID=211061;CLNDISDB=MedGen:CN517202|MONDO:MONDO:0009101,MedGen:C4551693,OMIM:222300,Orphanet:3463;CLNDN=not_provided|Wolfram_syndrome_1;CLNHGVS=NC_000004.12:g.6301479G>C;CLNREVSTAT=criteria_provided,_multiple_submitters,_no_conflicts;CLNSIG=Likely_pathogenic/Likely_risk_allele;CLNVC=single_nucleotide_variant;CLNVCSO=SO:0001483;CLNVI=ClinGen:CA322818;GENEINFO=WFS1:7466;MC=SO:0001583|missense_variant;ORIGIN=1;RS=753237278 + + //CLNSIGINCL=424752:Pathogenic //CLNSIGINCL=15127:other|15128:other|15334:Pathogenic|15335:Pathogenic|15336:Pathogenic|15337:Pathogenic|15610:Pathogenic|15612:other @@ -217,5 +280,153 @@ void testParseClinSigConf() { //CLNVC counts: Deletion=22574, Duplication=9075, Indel=2162, Insertion=2358, Inversion=32, Microsatellite=15, Variation=9, copy_number_loss=4, single_nucleotide_variant=264009 //CLNREVSTAT counts: criteria_provided,_conflicting_interpretations=12678, criteria_provided,_multiple_submitters,_no_conflicts=34967, criteria_provided,_single_submitter=197277, no_assertion_criteria_provided=34308, no_assertion_provided=10980, no_interpretation_for_the_single_variant=500, practice_guideline=23, reviewed_by_expert_panel=8786 + + @Disabled("data exploration") + @Test + void testClnSigValues() { + Path clinVarVcfFile = Path.of("clinvar_hg38.vcf.gz"); + var infoFieldCounts = getInfoFieldCounts(clinVarVcfFile, "CLNSIG"); + for (Map.Entry entry : infoFieldCounts.entrySet()) { + System.out.println(entry); + } + //##fileDate=2024-05-09 + //##INFO= + //Affects=142 + //Affects|risk_factor=1 + //Benign=202927 + //Benign/Likely_benign=48319 + //Benign/Likely_benign|association=1 + //Benign/Likely_benign|drug_response=2 + //Benign/Likely_benign|drug_response|other=3 + //Benign/Likely_benign|other=9 + //Benign/Likely_benign|other|risk_factor=1 + //Benign/Likely_benign|risk_factor=2 + //Benign|Affects=1 + //Benign|association=5 + //Benign|confers_sensitivity=2 + //Benign|drug_response=2 + //Benign|other=9 + //Benign|risk_factor=3 + //Conflicting_classifications_of_pathogenicity=125784 + //Conflicting_classifications_of_pathogenicity|Affects=2 + //Conflicting_classifications_of_pathogenicity|association=8 + //Conflicting_classifications_of_pathogenicity|association|risk_factor=2 + //Conflicting_classifications_of_pathogenicity|drug_response=2 + //Conflicting_classifications_of_pathogenicity|drug_response|other=1 + //Conflicting_classifications_of_pathogenicity|other=25 + //Conflicting_classifications_of_pathogenicity|other|risk_factor=2 + //Conflicting_classifications_of_pathogenicity|protective=1 + //Conflicting_classifications_of_pathogenicity|risk_factor=15 + //Likely_benign=874860 + //Likely_benign|association=1 + //Likely_benign|drug_response|other=4 + //Likely_benign|other=12 + //Likely_benign|risk_factor=1 + //Likely_pathogenic=82058 + //Likely_pathogenic,_low_penetrance=6 + //Likely_pathogenic/Likely_risk_allele=17 + //Likely_pathogenic|Affects=1 + //Likely_pathogenic|association=5 + //Likely_pathogenic|drug_response=21 + //Likely_pathogenic|other=2 + //Likely_pathogenic|protective=1 + //Likely_pathogenic|risk_factor=10 + //Likely_risk_allele=97 + //Pathogenic=157595 + //Pathogenic/Likely_pathogenic=26459 + //Pathogenic/Likely_pathogenic/Likely_risk_allele=4 + //Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance=6 + //Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance/Established_risk_allele=1 + //Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance|other=1 + //Pathogenic/Likely_pathogenic|drug_response=3 + //Pathogenic/Likely_pathogenic|other=11 + //Pathogenic/Likely_pathogenic|risk_factor=6 + //Pathogenic/Likely_risk_allele=9 + //Pathogenic/Likely_risk_allele|risk_factor=1 + //Pathogenic/Pathogenic,_low_penetrance|other=1 + //Pathogenic/Pathogenic,_low_penetrance|other|risk_factor=1 + //Pathogenic|Affects=6 + //Pathogenic|association=6 + //Pathogenic|association|protective=1 + //Pathogenic|confers_sensitivity=1 + //Pathogenic|drug_response=54 + //Pathogenic|other=71 + //Pathogenic|protective=2 + //Pathogenic|risk_factor=22 + //Uncertain_risk_allele=35 + //Uncertain_risk_allele|risk_factor=1 + //Uncertain_significance=1358995 + //Uncertain_significance/Uncertain_risk_allele=153 + //Uncertain_significance|association=8 + //Uncertain_significance|drug_response=11 + //Uncertain_significance|other=4 + //Uncertain_significance|risk_factor=7 + //association=341 + //association_not_found=4 + //association|drug_response|risk_factor=1 + //association|risk_factor=1 + //confers_sensitivity=11 + //confers_sensitivity|other=1 + //drug_response=1869 + //drug_response|other=1 + //drug_response|risk_factor=3 + //no_classification_for_the_single_variant=683 + //no_classifications_from_unflagged_records=7 + //not_provided=9808 + //other=1588 + //other|risk_factor=1 + //protective=39 + //protective|risk_factor=4 + //risk_factor=407 + } + + @Disabled("data exploration") + @Test + void testClnRevStatValues() { + Path clinVarVcfFile = Path.of("clinvar.vcf.gz"); + var infoFieldCounts = getInfoFieldCounts(clinVarVcfFile, "CLNREVSTAT"); + for (Map.Entry entry : infoFieldCounts.entrySet()) { + System.out.println(entry); + } + //##fileDate=2024-05-09 + //##INFO= + //criteria_provided,_conflicting_classifications=125583 + //criteria_provided,_multiple_submitters,_no_conflicts=425991 + //criteria_provided,_single_submitter=2266963 + //no_assertion_criteria_provided=48407 + //no_classification_for_the_single_variant=683 + //no_classification_provided=9806 + //no_classifications_from_unflagged_records=13 + //practice_guideline=51 + //reviewed_by_expert_panel=16215 + } + + private Map getInfoFieldCounts(Path clinVarVcfFile, String infoKey) { + try (Stream lines = new BufferedReader(new InputStreamReader(new BufferedInputStream(new GZIPInputStream(Files.newInputStream(clinVarVcfFile))))).lines()) { + var result = lines + .peek(line -> {if (line.startsWith("#")) {System.out.println(line);}}) + .filter(line -> !line.startsWith("#")) + .map(findInfoField(infoKey)) + .collect(Collectors.groupingBy(Function.identity(), Collectors.counting())); + return new TreeMap<>(result); + } catch (IOException e) { + System.err.println(e); + } + return Map.of(); + } + + private Function findInfoField(String infoKey) { + return line -> { + var fields = line.split("\t"); + var info= fields[7]; + var infoFields = info.split(";"); + for (String field : infoFields) { + if (field.startsWith(infoKey)) { + return field.split("=")[1]; + } + } + return ""; + }; + } } From 16bafc57adaa4cbbc4f02f4edbcd512fb93ac783 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Mon, 10 Jun 2024 15:04:16 +0100 Subject: [PATCH 05/21] Update splice-ai ingest in exomiser-data-genome for better typing and fix broken tests Update exomiser-data-genome to add gnomAD v4.1 data --- .../exomiser/data/genome/config/Hg19Config.java | 2 +- .../exomiser/data/genome/config/Hg38Config.java | 2 +- .../src/main/resources/application.properties | 10 ++++++---- .../exomiser/data/genome/config/Hg19ConfigTest.java | 1 + .../exomiser/data/genome/config/Hg38ConfigTest.java | 1 + .../src/test/resources/application-test.properties | 13 ++++++++++++- 6 files changed, 22 insertions(+), 7 deletions(-) diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg19Config.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg19Config.java index 540f21883..31f86c9ed 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg19Config.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg19Config.java @@ -93,7 +93,7 @@ public Map hg19AlleleResources() { return alleleResources.build(); } - private AlleleResource spliceAiAlleleResource() { + public SpliceAiAlleleResource spliceAiAlleleResource() { return alleleResource(SpliceAiAlleleResource.class, "hg19.splice-ai"); } diff --git a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java index dc165fd54..b78337d23 100644 --- a/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java +++ b/exomiser-data-genome/src/main/java/org/monarchinitiative/exomiser/data/genome/config/Hg38Config.java @@ -96,7 +96,7 @@ public Map hg38AlleleResources() { return alleleResources.build(); } - private AlleleResource spliceAiAlleleResource() { + public SpliceAiAlleleResource spliceAiAlleleResource() { return alleleResource(SpliceAiAlleleResource.class, "hg38.splice-ai"); } diff --git a/exomiser-data-genome/src/main/resources/application.properties b/exomiser-data-genome/src/main/resources/application.properties index 400c4f795..7da65c540 100644 --- a/exomiser-data-genome/src/main/resources/application.properties +++ b/exomiser-data-genome/src/main/resources/application.properties @@ -19,6 +19,8 @@ # spring.flyway.enabled=false spring.h2.console.enabled=true +logging.file.path=${build-dir} + # build-dir defines the main directory which will be used to build the databases. build-dir=. build-version=1711 @@ -62,7 +64,7 @@ hg19.uk10k.file-dir=${hg19.variant-dir} hg19.dbnsfp.file-name=dbNSFP4.5a.zip hg19.dbnsfp.file-url=ftp://dbnsfp:dbnsfp@dbnsfp.softgenetics.com/ hg19.dbnsfp.file-dir=${hg19.variant-dir} -# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg19.vcf.gz to only include variants max(delta_score) >= 2.0 +# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg19.vcf.gz to only include variants max(delta_score) >= 1.0 hg19.splice-ai.file-name=spliceai_max_delta_scores_non_zero.masked.snv.hg19.vcf.gz hg19.splice-ai.file-url=file://${hg19.variant-dir} hg19.splice-ai.file-dir=${hg19.variant-dir} @@ -73,11 +75,11 @@ hg38.variant-processed-dir=${hg38.variant-dir}/processed hg38.genome-dir=${build-dir}/hg38/genome hg38.genome-processed-dir=${hg38.genome-dir}/processed hg38.ensembl-variation-url=http://ftp.ensembl.org/pub/data_files/homo_sapiens/GRCh38/variation_genotype/ -hg38.gnomad-exome.file-name=gnomad-v4/exomes +hg38.gnomad-exome.file-name=gnomad-v4-1/exomes hg38.gnomad-exome.file-url=https://storage.googleapis.com/gcp-public-data--gnomad/release/2.1.1/liftover_grch38/vcf/exomes/ hg38.gnomad-exome.file-dir=${hg38.variant-dir} # hg38.gnomad-genome.file-name should be a directory containing the gnomad.genomes.v3.1.2.sites.chr$i.vcf.bgz files -hg38.gnomad-genome.file-name=gnomad-v4/genomes +hg38.gnomad-genome.file-name=gnomad-v4-1/genomes hg38.gnomad-genome.file-url=https://storage.googleapis.com/gcp-public-data--gnomad/release/3.1.2/vcf/genomes/gnomad.genomes.v3.1.2.sites.chr1.vcf.bgz hg38.gnomad-genome.file-dir=${hg38.variant-dir} hg38.gnomad-mito.file-name=gnomad.genomes.v3.1.sites.chrM.vcf.bgz @@ -110,7 +112,7 @@ hg38.uk10k.file-dir=${hg38.variant-dir} hg38.dbnsfp.file-name=${hg19.dbnsfp.file-name} hg38.dbnsfp.file-url=${hg19.dbnsfp.file-url} hg38.dbnsfp.file-dir=${hg19.variant-dir} -# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg38.vcf.gz to only include variants max(delta_score) >= 2.0 +# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg38.vcf.gz to only include variants max(delta_score) >= 1.0 hg38.splice-ai.file-name=spliceai_max_delta_scores_non_zero.masked.snv.hg38.vcf.gz hg38.splice-ai.file-url=file://${hg38.variant-dir} hg38.splice-ai.file-dir=${hg38.variant-dir} diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg19ConfigTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg19ConfigTest.java index 4c0137223..16a14dfa0 100644 --- a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg19ConfigTest.java +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg19ConfigTest.java @@ -87,6 +87,7 @@ public void testResources() { // exac removed as this is part of gnomad alleleResources.put("esp", instance.espAlleleResource()); alleleResources.put("dbnsfp", instance.dbnsfpAlleleResource()); + alleleResources.put("splice-ai", instance.spliceAiAlleleResource()); Map expectedResources = alleleResources.build(); diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg38ConfigTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg38ConfigTest.java index c7accf5e4..ca58e094d 100644 --- a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg38ConfigTest.java +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/config/Hg38ConfigTest.java @@ -88,6 +88,7 @@ public void testResources() { // esp removed as this is part of gnomad since v4 alleleResources.put("dbnsfp", instance.dbnsfpAlleleResource()); // clinvar removed as this is now standalone + alleleResources.put("splice-ai", instance.spliceAiAlleleResource()); Map expectedResources = alleleResources.build(); diff --git a/exomiser-data-genome/src/test/resources/application-test.properties b/exomiser-data-genome/src/test/resources/application-test.properties index f7154636f..a0ca8ee8c 100644 --- a/exomiser-data-genome/src/test/resources/application-test.properties +++ b/exomiser-data-genome/src/test/resources/application-test.properties @@ -19,6 +19,8 @@ # spring.flyway.enabled=false spring.h2.console.enabled=true +logging.file.path=${build-dir} + #build-dir defines the main directory which will be used to build the databases. build-dir=src/test/resources build-version=1711 @@ -60,6 +62,11 @@ hg19.uk10k.file-url=${hg19.ensembl-variation-url} hg19.dbnsfp.file-name=dbNSFPv3.4a.zip hg19.dbnsfp.file-dir=${hg19.variant-dir} hg19.dbnsfp.file-url=ftp://dbnsfp:dbnsfp@dbnsfp.softgenetics.com/ +# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg19.vcf.gz to only include variants max(delta_score) >= 1.0 +hg19.splice-ai.file-name=spliceai_max_delta_scores_non_zero.masked.snv.hg19.vcf.gz +hg19.splice-ai.file-url=file://${hg19.variant-dir} +hg19.splice-ai.file-dir=${hg19.variant-dir} + #hg38 hg38.variant-dir=${build-dir}/hg38/variants hg38.variant-processed-dir=${hg38.variant-dir}/processed @@ -101,4 +108,8 @@ hg38.uk10k.file-url=${hg38.ensembl-variation-url} #DbNSFP contains the hg19 and hg38 coordinates in the same file hg38.dbnsfp.file-name=${hg19.dbnsfp.file-name} hg38.dbnsfp.file-dir=${hg19.dbnsfp.file-dir} -hg38.dbnsfp.file-url=${hg19.dbnsfp.file-url} \ No newline at end of file +hg38.dbnsfp.file-url=${hg19.dbnsfp.file-url} +# The spliceAI file has been processed from the original spliceai_scores.masked.snv.hg38.vcf.gz to only include variants max(delta_score) >= 1.0 +hg38.splice-ai.file-name=spliceai_max_delta_scores_non_zero.masked.snv.hg38.vcf.gz +hg38.splice-ai.file-url=file://${hg38.variant-dir} +hg38.splice-ai.file-dir=${hg38.variant-dir} \ No newline at end of file From 31ba09f8738640ecf21aad5bae9d72a94ed2886d Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Thu, 22 Aug 2024 16:36:54 +0100 Subject: [PATCH 06/21] Add new AcmgEvidence.parseAcmgEvidence() method --- .../analysis/util/acmg/AcmgCriterion.java | 12 ++--- .../core/analysis/util/acmg/AcmgEvidence.java | 27 ++++++++++ .../analysis/util/acmg/AcmgEvidenceTest.java | 53 +++++++++++++------ 3 files changed, 71 insertions(+), 21 deletions(-) diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgCriterion.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgCriterion.java index 9d6b328c0..a72284b03 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgCriterion.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgCriterion.java @@ -79,12 +79,12 @@ public static Evidence parseValue(String displayString) { } catch (IllegalArgumentException ex) { // swallow and try the display string } - return switch (displayString) { - case "StandAlone" -> STAND_ALONE; - case "VeryStrong" -> VERY_STRONG; - case "Strong" -> STRONG; - case "Moderate" -> MODERATE; - case "Supporting" -> SUPPORTING; + return switch (displayString.toLowerCase()) { + case "standalone" -> STAND_ALONE; + case "verystrong" -> VERY_STRONG; + case "strong" -> STRONG; + case "moderate" -> MODERATE; + case "supporting" -> SUPPORTING; default -> throw new IllegalArgumentException("Unrecognised evidence value '" + displayString + "'"); }; } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java index 4d41544fd..57ce72482 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidence.java @@ -246,6 +246,24 @@ public String toString() { return '[' + stringJoiner.toString() + ']'; } + public static AcmgEvidence parseAcmgEvidence(String criteria) { + if (criteria == null || criteria.isEmpty()) { + return AcmgEvidence.empty(); + } + AcmgEvidence.Builder acmgEvidenceBuilder = AcmgEvidence.builder(); + for (String criterion : criteria.replace("[", "").replace("]", "").split("[, ]+")) { + String[] criteriaModifier = criterion.trim().split("_"); + AcmgCriterion acmgCriterion = AcmgCriterion.valueOf(criteriaModifier[0]); + if (criteriaModifier.length == 2) { + AcmgCriterion.Evidence modifier = AcmgCriterion.Evidence.parseValue(criteriaModifier[1]); + acmgEvidenceBuilder.add(acmgCriterion, modifier); + } else { + acmgEvidenceBuilder.add(acmgCriterion); + } + } + return acmgEvidenceBuilder.build(); + } + public static class Builder { private final EnumMap evidence = new EnumMap<>(AcmgCriterion.class); @@ -268,6 +286,15 @@ public boolean containsWithEvidence(AcmgCriterion acmgCriterion, Evidence eviden return evidence.containsKey(acmgCriterion) && evidence.get(acmgCriterion) == evidenceStrength; } + public void remove(AcmgCriterion acmgCriterion) { + evidence.remove(acmgCriterion); + } + + @Nullable + public Evidence evidenceForCategory(AcmgCriterion acmgCriterion) { + return evidence.get(acmgCriterion); + } + public AcmgEvidence build() { return evidence.isEmpty() ? EMPTY : new AcmgEvidence(evidence); } diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java index 6a430a63d..912c7110f 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgEvidenceTest.java @@ -31,7 +31,7 @@ import static org.hamcrest.Matchers.equalTo; import static org.monarchinitiative.exomiser.core.analysis.util.acmg.AcmgCriterion.*; -public class AcmgEvidenceTest { +class AcmgEvidenceTest { @Test void testEmptyBuilder() { @@ -50,13 +50,13 @@ void testStaticFactoryDefaultEvidence() { } @Test - public void testToStringDefaultEvidence() { + void testToStringDefaultEvidence() { AcmgEvidence instance = AcmgEvidence.builder().add(PVS1).add(PS1).build(); assertThat(instance.toString(), equalTo("[PVS1, PS1]")); } @Test - public void testToStringModifiedEvidence() { + void testToStringModifiedEvidence() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1, Evidence.STRONG) .add(PS1, Evidence.MODERATE) @@ -65,8 +65,31 @@ public void testToStringModifiedEvidence() { assertThat(instance.toString(), equalTo("[PVS1_Strong, PS1_Moderate, PP3_VeryStrong]")); } + @ParameterizedTest + @CsvSource(value = { + "'[PVS1, PS1_Moderate, PP3_VeryStrong]'", + "'[PVS1,PS1_Moderate,PP3_VeryStrong]'", + "'PVS1, PS1_Moderate, PP3_VeryStrong'", + "'PVS1 PS1_Moderate PP3_VeryStrong'", + "'[PVS1 PS1_Moderate PP3_VeryStrong['", + // stupid shit + "'PVS1 PS1_Moderate PP3_VeryStrong'", + "'PVS1 PS1_Moderate PP3_VERYSTRONG'", + "'PVS1 PS1_Moderate PP3_verystrong'", + "'PVS1 PS1_Moderate, PP3_verystrong'", + "'PVS1 PS1_Moderate,PP3_verystrong'", + }) + void testParseEvidence(String acmgEvidence) { + AcmgEvidence expected = AcmgEvidence.builder() + .add(PVS1) + .add(PS1, Evidence.MODERATE) + .add(PP3, Evidence.VERY_STRONG) + .build(); + assertThat(AcmgEvidence.parseAcmgEvidence(acmgEvidence), equalTo(expected)); + } + @Test - public void testGetEvidenceOverwriteInputInBuilder() { + void testGetEvidenceOverwriteInputInBuilder() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1, Evidence.STRONG) .add(PVS1) @@ -75,7 +98,7 @@ public void testGetEvidenceOverwriteInputInBuilder() { } @Test - public void testGetEvidenceDefaultValue() { + void testGetEvidenceDefaultValue() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1) .build(); @@ -83,7 +106,7 @@ public void testGetEvidenceDefaultValue() { } @Test - public void testGetEvidenceModifiedValue() { + void testGetEvidenceModifiedValue() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1, Evidence.MODERATE) .build(); @@ -91,7 +114,7 @@ public void testGetEvidenceModifiedValue() { } @Test - public void testGetEvidenceNoValue() { + void testGetEvidenceNoValue() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1, Evidence.MODERATE) .build(); @@ -99,7 +122,7 @@ public void testGetEvidenceNoValue() { } @Test - public void testContainsEvidence() { + void testContainsEvidence() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1, Evidence.MODERATE) .build(); @@ -108,7 +131,7 @@ public void testContainsEvidence() { } @Test - public void testBuilderContainsEvidence() { + void testBuilderContainsEvidence() { AcmgEvidence.Builder instance = AcmgEvidence.builder() .add(PVS1, Evidence.MODERATE); assertThat(instance.contains(PVS1), equalTo(true)); @@ -116,7 +139,7 @@ public void testBuilderContainsEvidence() { } @Test - public void testBuilderContainsEvidenceWithStrength() { + void testBuilderContainsEvidenceWithStrength() { AcmgEvidence.Builder instance = AcmgEvidence.builder() .add(PVS1, Evidence.MODERATE); assertThat(instance.containsWithEvidence(PVS1, Evidence.MODERATE), equalTo(true)); @@ -125,13 +148,13 @@ public void testBuilderContainsEvidenceWithStrength() { } @Test - public void testSizeWhenEmpty() { + void testSizeWhenEmpty() { AcmgEvidence instance = AcmgEvidence.builder().build(); assertThat(instance.size(), equalTo(0)); } @Test - public void testSizeWithElement() { + void testSizeWithElement() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1) .build(); @@ -139,13 +162,13 @@ public void testSizeWithElement() { } @Test - public void testIsEmpty() { + void testIsEmpty() { AcmgEvidence instance = AcmgEvidence.builder().build(); assertThat(instance.isEmpty(), equalTo(true)); } @Test - public void testNotEmpty() { + void testNotEmpty() { AcmgEvidence instance = AcmgEvidence.builder() .add(PVS1) .build(); @@ -253,7 +276,7 @@ void testEvidence() { "BA1, -8, 0.000", // BA1 is a bit of an anomaly - it's intended as a hard filter, so doesn't fit into the points system }) void testPosteriorProb(String criteria, int points, double posteriorProb) { - AcmgEvidence acmgEvidence = parseAcmgEvidence(criteria); + AcmgEvidence acmgEvidence = AcmgEvidence.parseAcmgEvidence(criteria); assertThat(acmgEvidence.points(), equalTo(points)); assertThat(acmgEvidence.postProbPath(), closeTo(posteriorProb, 0.001)); } From 2d3e69d75cf19b19df164b91d2c20ecea0b60ec0 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Fri, 23 Aug 2024 12:19:48 +0100 Subject: [PATCH 07/21] Fix for issue #565 ArrayIndexOutOfBoundsException in FrequencyData.maxFrequency() --- .../core/model/frequency/FrequencyData.java | 21 ++++++++------- .../model/frequency/FrequencyDataTest.java | 26 ++++++++++++++----- 2 files changed, 32 insertions(+), 15 deletions(-) diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyData.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyData.java index 6c11dd277..8b3cb47da 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyData.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyData.java @@ -324,7 +324,7 @@ public float maxFreq() { @JsonIgnore @Nullable public Frequency maxFrequency() { - return this.size == 0 ? null : frequency(maxSource); + return maxSource == -1 ? null : frequency(maxSource); } /** @@ -454,10 +454,11 @@ public Builder addFrequency(FrequencySource frequencySource, int ac, int an, int */ private Builder addFrequency(FrequencySource frequencySource, float frequency, int ac, int an, int homCount) { frequencySources[frequencySource.ordinal()] = frequencySource; - frequencyData[frequencySource.ordinal() * WORD_SIZE + FREQ_OFFSET] = frequency; - frequencyData[frequencySource.ordinal() * WORD_SIZE + AC_OFFSET] = ac; - frequencyData[frequencySource.ordinal() * WORD_SIZE + AN_OFFSET] = an; - frequencyData[frequencySource.ordinal() * WORD_SIZE + HOM_OFFSET] = homCount; + int freqIndex = frequencySource.ordinal() * WORD_SIZE; + frequencyData[freqIndex + FREQ_OFFSET] = frequency; + frequencyData[freqIndex + AC_OFFSET] = ac; + frequencyData[freqIndex + AN_OFFSET] = an; + frequencyData[freqIndex + HOM_OFFSET] = homCount; return this; } @@ -517,10 +518,12 @@ public FrequencyData build() { FrequencySource source = values[i]; if (frequencySources[source.ordinal()] != null) { sources[dataPos] = source; - data[dataPos * WORD_SIZE + FREQ_OFFSET] = frequencyData[source.ordinal() * WORD_SIZE + FREQ_OFFSET]; - data[dataPos * WORD_SIZE + AC_OFFSET] = frequencyData[source.ordinal() * WORD_SIZE + AC_OFFSET]; - data[dataPos * WORD_SIZE + AN_OFFSET] = frequencyData[source.ordinal() * WORD_SIZE + AN_OFFSET]; - data[dataPos * WORD_SIZE + HOM_OFFSET] = frequencyData[source.ordinal() * WORD_SIZE + HOM_OFFSET]; + int dataIndex = dataPos * WORD_SIZE; + int freqIndex = source.ordinal() * WORD_SIZE; + data[dataIndex + FREQ_OFFSET] = frequencyData[freqIndex + FREQ_OFFSET]; + data[dataIndex + AC_OFFSET] = frequencyData[freqIndex + AC_OFFSET]; + data[dataIndex + AN_OFFSET] = frequencyData[freqIndex + AN_OFFSET]; + data[dataIndex + HOM_OFFSET] = frequencyData[freqIndex + HOM_OFFSET]; dataPos++; } } diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyDataTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyDataTest.java index 1f09347aa..8db886462 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyDataTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/frequency/FrequencyDataTest.java @@ -26,12 +26,15 @@ package org.monarchinitiative.exomiser.core.model.frequency; +import org.h2.mvstore.MVStore; +import org.junit.jupiter.api.Disabled; import org.junit.jupiter.api.Test; +import org.monarchinitiative.exomiser.core.genome.dao.serialisers.MvStoreUtil; +import org.monarchinitiative.exomiser.core.model.AlleleProtoAdaptor; +import org.monarchinitiative.exomiser.core.proto.AlleleProto; +import org.monarchinitiative.exomiser.core.proto.AlleleProtoFormatter; -import java.util.ArrayList; -import java.util.Collections; -import java.util.List; -import java.util.Set; +import java.util.*; import static org.hamcrest.CoreMatchers.equalTo; import static org.hamcrest.CoreMatchers.is; @@ -287,6 +290,17 @@ public void testGetMaxFrequencyWithData() { assertThat(instance.maxFrequency(), equalTo(maxFrequency)); } + @Test + public void testGetMaxFrequencyWhenZeroData() { + Frequency maxFrequency = Frequency.of(GNOMAD_E_AFR, 0, 1000, 0); + Frequency minFrequency = Frequency.of(TOPMED, 0f); + FrequencyData instance = FrequencyData.of("rs545662810", minFrequency, maxFrequency); + + assertThat(instance.maxFrequency(), equalTo(null)); + assertThat(instance.maxFreq(), equalTo(0f)); + assertThat(instance.frequencies(), equalTo(List.of(minFrequency, maxFrequency))); + } + @Test public void testHasFrequencyOverPercentageValue() { float maxFreq = 0.05f; @@ -482,12 +496,12 @@ void floatArray() { var an = 10000; var hom = 10; var af = Frequency.percentageFrequency(ac, an); - System.out.println("AF=" + af); + data[0] = (float) ac; data[1] = (float) an; data[2] = (float) hom; data[3] = (float) af; - System.out.println("dataAF=" + data[3]); + assertThat(Frequency.percentageFrequency((int) data[0], (int) data[1]), equalTo((float) data[3])); } From f8c08eb0674e70ed9ee1ece8bdb86251821b0dc5 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Mon, 2 Sep 2024 10:14:45 +0100 Subject: [PATCH 08/21] Add new GeneStatistics class for handling aggregated ClinVar gene-level variant effect counts. --- .../exomiser/core/model/GeneStatistics.java | 273 ++++++++++++++++++ .../core/model/GeneStatisticsTest.java | 116 ++++++++ 2 files changed, 389 insertions(+) create mode 100644 exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/GeneStatistics.java create mode 100644 exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/GeneStatisticsTest.java diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/GeneStatistics.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/GeneStatistics.java new file mode 100644 index 000000000..8ffe93c6d --- /dev/null +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/GeneStatistics.java @@ -0,0 +1,273 @@ +package org.monarchinitiative.exomiser.core.model; + +import de.charite.compbio.jannovar.annotation.VariantEffect; +import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData; + +import java.util.EnumMap; +import java.util.Map; +import java.util.StringJoiner; + +import static de.charite.compbio.jannovar.annotation.VariantEffect.*; + +/** + * Data class for collating ClinVar pathogenicity assertions against variant effect, primarily for the application of + * ACMG criteria BP1 and PP2. + * + * @since 14.1.0 + */ +public class GeneStatistics { + + private static final int PATH_INDEX = 0; + private static final int VUS_INDEX = 1; + private static final int BENIGN_INDEX = 2; + + private static final VariantEffect[] LOF_EFFECTS = { + STOP_LOST, STOP_GAINED, FRAMESHIFT_ELONGATION, FRAMESHIFT_TRUNCATION, FRAMESHIFT_VARIANT, + SPLICE_DONOR_VARIANT, SPLICE_ACCEPTOR_VARIANT, + TRANSCRIPT_ABLATION, EXON_LOSS_VARIANT, + START_LOST + }; + + private final String geneSymbol; + private final Map clinVarCounts; + + private GeneStatistics(String geneSymbol, Map clinVarCounts) { + this.geneSymbol = geneSymbol; + this.clinVarCounts = clinVarCounts; + } + + /** + * @return The gene symbol for the gene related to these statistics + */ + public String geneSymbol() { + return geneSymbol; + } + + /** + * @return The sum of all pathogenic / likely pathogenic variants associated with this gene. + */ + public int pathCount() { + return totalCountForIndex(PATH_INDEX); + } + + /** + * @return The sum of all variants of uncertain significance (VUS) associated with this gene. + */ + public int vusCount() { + return totalCountForIndex(VUS_INDEX); + } + + /** + * @return The sum of all benign / likely benign variants associated with this gene. + */ + public int benignCount() { + return totalCountForIndex(BENIGN_INDEX); + } + + private int totalCountForIndex(int i) { + int count = 0; + for (Map.Entry variantEffectEntry : clinVarCounts.entrySet()) { + count += variantEffectEntry.getValue()[i]; + } + return count; + } + + /** + * The sum of all pathogenic / likely pathogenic Loss Of Function variants associated with this gene. These are + * defined here as: + * 
+     *      STOP_LOST, STOP_GAINED, FRAMESHIFT_ELONGATION, FRAMESHIFT_TRUNCATION, FRAMESHIFT_VARIANT,
+     *      SPLICE_DONOR_VARIANT, SPLICE_ACCEPTOR_VARIANT,
+     *      TRANSCRIPT_ABLATION, EXON_LOSS_VARIANT,
+     *      START_LOST
+     *
+ * + * @return The sum of all pathogenic / likely pathogenic Loss Of Function variants associated with this gene. + */ + public int lofPathCount() { + return pathCount(LOF_EFFECTS); + } + + /** + * The sum of all variants of uncertain significance (VUS) Loss Of Function variants associated with this gene. These are + * defined here as: + * 
+     *      STOP_LOST, STOP_GAINED, FRAMESHIFT_ELONGATION, FRAMESHIFT_TRUNCATION, FRAMESHIFT_VARIANT,
+     *      SPLICE_DONOR_VARIANT, SPLICE_ACCEPTOR_VARIANT,
+     *      TRANSCRIPT_ABLATION, EXON_LOSS_VARIANT,
+     *      START_LOST
+     *
+ * + * @return The sum of all variants of uncertain significance (VUS) Loss Of Function variants associated with this gene. + */ + public int lofVusCount() { + return vusCount(LOF_EFFECTS); + } + + /** + * The sum of all benign / likely benign Loss Of Function variants associated with this gene. These are defined here + * as: + * 
+     *      STOP_LOST, STOP_GAINED, FRAMESHIFT_ELONGATION, FRAMESHIFT_TRUNCATION, FRAMESHIFT_VARIANT,
+     *      SPLICE_DONOR_VARIANT, SPLICE_ACCEPTOR_VARIANT,
+     *      TRANSCRIPT_ABLATION, EXON_LOSS_VARIANT,
+     *      START_LOST
+     *
+ * + * @return The sum of all benign / likely benign Loss Of Function variants associated with this gene. + */ + public int lofBenignCount() { + return benignCount(LOF_EFFECTS); + } + + /** + * @return The sum of all pathogenic / likely pathogenic missense variants associated with this gene. + */ + public int missensePathCount() { + return pathCount(VariantEffect.MISSENSE_VARIANT); + } + + /** + * @return The sum of all VUS missense variants associated with this gene. + */ + public int missenseVusCount() { + return vusCount(VariantEffect.MISSENSE_VARIANT); + } + + /** + * @return The sum of all benign / likely benign missense variants associated with this gene. + */ + public int missenseBenignCount() { + return benignCount(VariantEffect.MISSENSE_VARIANT); + } + + /** + * @return The sum of all pathogenic / likely pathogenic variants for the given variantEffect associated with this gene. + */ + public int pathCount(VariantEffect variantEffect) { + return effectIndexCount(variantEffect, PATH_INDEX); + } + + /** + * @return The sum of all VUS variants for the given variantEffect associated with this gene. + */ + public int vusCount(VariantEffect variantEffect) { + return effectIndexCount(variantEffect, VUS_INDEX); + } + + /** + * @return The sum of all benign / likely benign variants for the given variantEffect associated with this gene. + */ + public int benignCount(VariantEffect variantEffect) { + return effectIndexCount(variantEffect, BENIGN_INDEX); + } + + /** + * @return The sum of all pathogenic / likely pathogenic variants for the given variantEffects associated with this gene. + */ + public int pathCount(VariantEffect... variantEffect) { + return effectIndexCounts(variantEffect, PATH_INDEX); + } + + /** + * @return The sum of all VUS variants for the given variantEffects associated with this gene. + */ + public int vusCount(VariantEffect... variantEffect) { + return effectIndexCounts(variantEffect, VUS_INDEX); + } + + /** + * @return The sum of all benign / likely benign variants for the given variantEffects associated with this gene. + */ + public int benignCount(VariantEffect... variantEffect) { + return effectIndexCounts(variantEffect, BENIGN_INDEX); + } + + private int effectIndexCounts(VariantEffect[] variantEffect, int index) { + int count = 0; + for (int i = 0; i < variantEffect.length; i++) { + count += effectIndexCount(variantEffect[i], index); + } + return count; + } + + private int effectIndexCount(VariantEffect variantEffect, int i) { + return clinVarCounts.getOrDefault(variantEffect, new int[3])[i]; + } + + @Override + public String toString() { + StringBuilder statsBuilder = new StringBuilder("{"); + clinVarCounts.forEach((key, value) -> statsBuilder.append(key).append("=").append("[").append(prettyStats(value)).append("], ")); + if (statsBuilder.length() > 1) { + statsBuilder.delete(statsBuilder.length() - 2, statsBuilder.length()); + } + statsBuilder.append("}"); + return "GeneStatistics{" + + "geneSymbol=" + geneSymbol + ',' + + " counts=" + statsBuilder + + '}'; + } + + private static final String[] categories = {"P", "VUS", "B"}; + + private String prettyStats(int[] counts) { + StringJoiner countStr = new StringJoiner(", "); + for (int i = 0; i < 3; i++) { + countStr.add(categories[i] + "=" + counts[i]); + } + return countStr.toString(); + } + + public static Builder builder(String geneSymbol) { + return new Builder(geneSymbol); + } + + public static Builder builder(String geneSymbol, VariantEffect variantEffect, ClinVarData.ClinSig clinSig) { + return new Builder(geneSymbol, variantEffect, clinSig); + } + + public static class Builder { + + private final String geneSymbol; + private final Map geneStats = new EnumMap<>(VariantEffect.class); + + public Builder(String geneSymbol) { + this.geneSymbol = geneSymbol; + } + + public Builder(String geneSymbol, VariantEffect variantEffect, ClinVarData.ClinSig clinSig) { + this.geneSymbol = geneSymbol; + put(variantEffect, clinSig); + } + + public Builder put(VariantEffect variantEffect, ClinVarData.ClinSig clinSig) { + int countIndex = getCountIndex(clinSig); + if (countIndex != -1) { + int[] counts = geneStats.get(variantEffect); + if (counts == null) { + counts = new int[3]; + counts[countIndex]++; + geneStats.put(variantEffect, counts); + } else { + counts[countIndex]++; + } + } + return this; + } + + private static int getCountIndex(ClinVarData.ClinSig clinSig) { + return switch (clinSig) { + case PATHOGENIC, PATHOGENIC_OR_LIKELY_PATHOGENIC, LIKELY_PATHOGENIC -> PATH_INDEX; + case UNCERTAIN_SIGNIFICANCE -> VUS_INDEX; + case LIKELY_BENIGN, BENIGN_OR_LIKELY_BENIGN, BENIGN -> BENIGN_INDEX; + default -> -1; + }; + } + + public GeneStatistics build() { + return new GeneStatistics(geneSymbol, geneStats); + } + } + +} diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/GeneStatisticsTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/GeneStatisticsTest.java new file mode 100644 index 000000000..e631e323d --- /dev/null +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/model/GeneStatisticsTest.java @@ -0,0 +1,116 @@ +package org.monarchinitiative.exomiser.core.model; + +import de.charite.compbio.jannovar.annotation.VariantEffect; +import org.junit.jupiter.api.Test; +import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData; + +import static de.charite.compbio.jannovar.annotation.VariantEffect.*; +import static org.hamcrest.MatcherAssert.assertThat; +import static org.hamcrest.Matchers.equalTo; + +class GeneStatisticsTest { + + @Test + void testBuilderNoStats() { + var instance = GeneStatistics.builder("WIBBLE").build(); + assertThat(instance.geneSymbol(), equalTo("WIBBLE")); + assertThat(instance.pathCount(), equalTo(0)); + assertThat(instance.vusCount(), equalTo(0)); + assertThat(instance.benignCount(), equalTo(0)); + } + + + @Test + void testBuilderStats() { + var instance = GeneStatistics.builder("WIBBLE") + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.LIKELY_PATHOGENIC) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.BENIGN) + // LOF effects + .put(VariantEffect.STOP_GAINED, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.STOP_LOST, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.SPLICE_ACCEPTOR_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.SPLICE_DONOR_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.EXON_LOSS_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.START_LOST, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.START_LOST, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(VariantEffect.TRANSCRIPT_ABLATION, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.FRAMESHIFT_ELONGATION, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.FRAMESHIFT_TRUNCATION, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.FRAMESHIFT_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + // other effect + .put(VariantEffect.INTRON_VARIANT, ClinVarData.ClinSig.BENIGN) + .build(); + assertThat(instance.geneSymbol(), equalTo("WIBBLE")); + assertThat(instance.pathCount(), equalTo(13)); + assertThat(instance.vusCount(), equalTo(3)); + assertThat(instance.benignCount(), equalTo(2)); + + assertThat(instance.missensePathCount(), equalTo(3)); + assertThat(instance.missenseVusCount(), equalTo(2)); + assertThat(instance.missenseBenignCount(), equalTo(1)); + + assertThat(instance.lofPathCount(), equalTo(10)); + assertThat(instance.lofVusCount(), equalTo(1)); + assertThat(instance.lofBenignCount(), equalTo(0)); + } + + @Test + void testIgnoresNonPathVusBenignStatus() { + var instance = GeneStatistics.builder("WIBBLE", MISSENSE_VARIANT, ClinVarData.ClinSig.ESTABLISHED_RISK_ALLELE).build(); + assertThat(instance.pathCount(), equalTo(0)); + assertThat(instance.vusCount(), equalTo(0)); + assertThat(instance.benignCount(), equalTo(0)); + + } + + @Test + void testToString() { + var instance = GeneStatistics.builder("WIBBLE") + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.LIKELY_PATHOGENIC) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(VariantEffect.MISSENSE_VARIANT, ClinVarData.ClinSig.BENIGN) + .put(VariantEffect.STOP_GAINED, ClinVarData.ClinSig.PATHOGENIC) + .put(VariantEffect.INTRON_VARIANT, ClinVarData.ClinSig.BENIGN) + .build(); + + var expected = "GeneStatistics{geneSymbol=WIBBLE, counts={STOP_GAINED=[P=1, VUS=0, B=0], MISSENSE_VARIANT=[P=3, VUS=2, B=1], INTRON_VARIANT=[P=0, VUS=0, B=1]}}"; + assertThat(instance.toString(), equalTo(expected)); + } + + @Test + void testEmptyString() { + assertThat(GeneStatistics.builder("WIBBLE").build().toString(), equalTo("GeneStatistics{geneSymbol=WIBBLE, counts={}}")); + } + + @Test + void testCanGetStatsForArbitraryVariantEffect() { + var instance = GeneStatistics.builder("WIBBLE") + .put(SYNONYMOUS_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .build(); + + assertThat(instance.vusCount(), equalTo(1)); + assertThat(instance.vusCount(SYNONYMOUS_VARIANT), equalTo(instance.vusCount())); + } + + @Test + void testCanGetStatsForArbitraryVariantEffects() { + var instance = GeneStatistics.builder("WIBBLE") + .put(FIVE_PRIME_UTR_EXON_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(INTRON_VARIANT, ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) + .put(MISSENSE_VARIANT, ClinVarData.ClinSig.PATHOGENIC) + .build(); + + assertThat(instance.vusCount(), equalTo(2)); + assertThat(instance.vusCount(FIVE_PRIME_UTR_EXON_VARIANT, INTRON_VARIANT, MISSENSE_VARIANT), equalTo(instance.vusCount())); + assertThat(instance.vusCount(FIVE_PRIME_UTR_EXON_VARIANT, INTRON_VARIANT), equalTo(instance.vusCount())); + assertThat(instance.pathCount(FIVE_PRIME_UTR_EXON_VARIANT, INTRON_VARIANT, MISSENSE_VARIANT), equalTo(instance.pathCount())); + assertThat(instance.pathCount(MISSENSE_VARIANT), equalTo(instance.pathCount())); + } +} \ No newline at end of file From 0c8df8fb07b2b817888770c5adc9ef6e70795f98 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Mon, 2 Sep 2024 10:18:23 +0100 Subject: [PATCH 09/21] Update ClinVarDao with new getGeneStatistics() method. --- .../genome/GenomeAnalysisServiceImpl.java | 13 +- .../core/genome/VariantDataServiceImpl.java | 14 +- .../exomiser/core/genome/dao/ClinVarDao.java | 11 +- .../core/genome/dao/ClinVarDaoMvStore.java | 35 +++- .../core/genome/TestVariantDataService.java | 62 +++++-- .../genome/VariantDataServiceImplTest.java | 2 +- .../genome/dao/ClinVarDaoMvStoreTest.java | 163 ++++++++++++++---- 7 files changed, 239 insertions(+), 61 deletions(-) diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/GenomeAnalysisServiceImpl.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/GenomeAnalysisServiceImpl.java index 84743ff79..8e86c6eb3 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/GenomeAnalysisServiceImpl.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/GenomeAnalysisServiceImpl.java @@ -20,6 +20,8 @@ package org.monarchinitiative.exomiser.core.genome; +import jakarta.annotation.Nonnull; +import org.monarchinitiative.exomiser.core.model.GeneStatistics; import org.monarchinitiative.exomiser.core.model.*; import org.monarchinitiative.exomiser.core.model.frequency.FrequencyData; import org.monarchinitiative.exomiser.core.model.frequency.FrequencySource; @@ -97,17 +99,22 @@ public PathogenicityData getVariantPathogenicityData(Variant variant, Set findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval) { + public Map findClinVarRecordsOverlappingInterval(@Nonnull GenomicInterval genomicInterval) { return variantDataService.findClinVarRecordsOverlappingInterval(genomicInterval); } + + @Override + public GeneStatistics getGeneStatistics(@Nonnull String geneSymbol) { + return variantDataService.getGeneStatistics(geneSymbol); + } } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java index 157c13531..b4b7b91d6 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImpl.java @@ -21,7 +21,8 @@ package org.monarchinitiative.exomiser.core.genome; -import de.charite.compbio.jannovar.annotation.VariantEffect; +import jakarta.annotation.Nonnull; +import org.monarchinitiative.exomiser.core.model.GeneStatistics; import org.monarchinitiative.exomiser.core.genome.dao.*; import org.monarchinitiative.exomiser.core.model.Variant; import org.monarchinitiative.exomiser.core.model.frequency.FrequencyData; @@ -182,20 +183,25 @@ private void addAllWantedScores(Set pathogenicitySources, P } @Override - public ClinVarData getClinVarData(Variant variant) { + public ClinVarData getClinVarData(@Nonnull Variant variant) { return clinVarDao.getClinVarData(variant); } @Override - public ClinVarData getClinVarData(GenomicVariant genomicVariant) { + public ClinVarData getClinVarData(@Nonnull GenomicVariant genomicVariant) { return clinVarDao.getClinVarData(genomicVariant); } @Override - public Map findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval) { + public Map findClinVarRecordsOverlappingInterval(@Nonnull GenomicInterval genomicInterval) { return clinVarDao.findClinVarRecordsOverlappingInterval(genomicInterval); } + @Override + public GeneStatistics getGeneStatistics(@Nonnull String geneSymbol) { + return clinVarDao.getGeneStatistics(geneSymbol); + } + public static Builder builder() { return new Builder(); } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDao.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDao.java index 6ad0f2d4f..5b8d8d755 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDao.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDao.java @@ -1,8 +1,9 @@ package org.monarchinitiative.exomiser.core.genome.dao; +import jakarta.annotation.Nonnull; +import org.monarchinitiative.exomiser.core.model.GeneStatistics; import org.monarchinitiative.exomiser.core.model.Variant; import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData; -import org.monarchinitiative.exomiser.core.proto.AlleleProto; import org.monarchinitiative.svart.GenomicInterval; import org.monarchinitiative.svart.GenomicVariant; @@ -16,9 +17,11 @@ */ public interface ClinVarDao { - ClinVarData getClinVarData(Variant variant); + ClinVarData getClinVarData(@Nonnull Variant variant); - ClinVarData getClinVarData(GenomicVariant genomicVariant); + ClinVarData getClinVarData(@Nonnull GenomicVariant genomicVariant); - Map findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval); + Map findClinVarRecordsOverlappingInterval(@Nonnull GenomicInterval genomicInterval); + + GeneStatistics getGeneStatistics(@Nonnull String geneSymbol); } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStore.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStore.java index c897599d6..00776b74f 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStore.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStore.java @@ -1,7 +1,9 @@ package org.monarchinitiative.exomiser.core.genome.dao; +import de.charite.compbio.jannovar.annotation.VariantEffect; import org.h2.mvstore.MVMap; import org.h2.mvstore.MVStore; +import org.monarchinitiative.exomiser.core.model.GeneStatistics; import org.monarchinitiative.exomiser.core.genome.dao.serialisers.MvStoreUtil; import org.monarchinitiative.exomiser.core.model.AlleleProtoAdaptor; import org.monarchinitiative.exomiser.core.model.Variant; @@ -12,10 +14,15 @@ import org.slf4j.LoggerFactory; import javax.annotation.Nonnull; +import java.time.Duration; +import java.time.Instant; +import java.util.HashMap; import java.util.Iterator; import java.util.LinkedHashMap; import java.util.Map; +import static org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData.ReviewStatus.CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS; + /** * @since 14.0.0 */ @@ -24,9 +31,30 @@ public class ClinVarDaoMvStore implements ClinVarDao { private static final Logger logger = LoggerFactory.getLogger(ClinVarDaoMvStore.class); private final MVMap clinVarMap; + private final Map geneStats; public ClinVarDaoMvStore(MVStore mvStore) { clinVarMap = MvStoreUtil.openClinVarMVMap(mvStore); + geneStats = calculateGeneStatistics(clinVarMap); + } + + private Map calculateGeneStatistics(MVMap clinVarMap) { + Instant start = Instant.now(); + Map geneStatisticsBuilders = new LinkedHashMap<>(1900); + for (Map.Entry entry : clinVarMap.entrySet()) { + AlleleProto.ClinVar clinVar = entry.getValue(); + ClinVarData.ReviewStatus reviewStatus = AlleleProtoAdaptor.toReviewStatus(clinVar.getReviewStatus()); + if (reviewStatus != CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS && reviewStatus.starRating() >= 1) { + VariantEffect variantEffect = AlleleProtoAdaptor.toVariantEffect(clinVar.getVariantEffect()); + ClinVarData.ClinSig clinSig = AlleleProtoAdaptor.toClinSig(clinVar.getPrimaryInterpretation()); + geneStatisticsBuilders.compute(clinVar.getGeneSymbol(), (k, v) -> (v == null) ? GeneStatistics.builder(k, variantEffect, clinSig) : v.put(variantEffect, clinSig)); + } + } + final Map stats = new HashMap<>(geneStatisticsBuilders.size()); + geneStatisticsBuilders.forEach((k, v) -> stats.put(k, v.build())); + Instant end = Instant.now(); + logger.info("Created {} ClinVar gene stats in {} ms", stats.size(), Duration.between(start, end).toMillis()); + return stats; } @Override @@ -45,7 +73,7 @@ private ClinVarData getClinVarData(@Nonnull AlleleProto.AlleleKey alleleKey) { } @Override - public Map findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval) { + public Map findClinVarRecordsOverlappingInterval(@Nonnull GenomicInterval genomicInterval) { Contig contig = genomicInterval.contig(); int chr = genomicInterval.contigId(); @@ -80,6 +108,11 @@ public Map findClinVarRecordsOverlappingInterval(Ge return results; } + @Override + public GeneStatistics getGeneStatistics(@Nonnull String geneSymbol) { + return geneStats.getOrDefault(geneSymbol, GeneStatistics.builder(geneSymbol).build()); + } + private String broadFormat(AlleleProto.AlleleKey alleleKey) { return alleleKey.getChr() + "-" + alleleKey.getPosition() + "-" + alleleKey.getRef() + "-" + alleleKey.getAlt(); } diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/TestVariantDataService.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/TestVariantDataService.java index 32ce1561b..c7967ae9d 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/TestVariantDataService.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/TestVariantDataService.java @@ -25,8 +25,8 @@ */ package org.monarchinitiative.exomiser.core.genome; -import com.google.common.collect.ImmutableMap; -import com.google.common.collect.ImmutableSet; +import jakarta.annotation.Nonnull; +import org.monarchinitiative.exomiser.core.model.GeneStatistics; import org.monarchinitiative.exomiser.core.model.Variant; import org.monarchinitiative.exomiser.core.model.frequency.Frequency; import org.monarchinitiative.exomiser.core.model.frequency.FrequencyData; @@ -55,11 +55,15 @@ public class TestVariantDataService implements VariantDataService { private final Set expectedWhiteList; private final Map expectedFrequencyData; private final Map expectedPathogenicityData; + private final Map expectedClinVarData; + private final Map expectedGeneStats; private TestVariantDataService(Builder builder) { - this.expectedWhiteList = ImmutableSet.copyOf(builder.expectedWhiteList); - this.expectedFrequencyData = ImmutableMap.copyOf(builder.expectedFrequencyData); - this.expectedPathogenicityData = ImmutableMap.copyOf(builder.expectedPathogenicityData); + this.expectedWhiteList = Set.copyOf(builder.expectedWhiteList); + this.expectedFrequencyData = Map.copyOf(builder.expectedFrequencyData); + this.expectedPathogenicityData = Map.copyOf(builder.expectedPathogenicityData); + this.expectedClinVarData = Map.copyOf(builder.expectedClinVarData); + this.expectedGeneStats = Map.copyOf(builder.expectedGeneStats); } /** @@ -105,7 +109,7 @@ public FrequencyData getVariantFrequencyData(Variant variant, Set wanted = allFrequencyData.frequencies() .stream() .filter(frequency -> frequencySources.contains(frequency.source())) - .collect(Collectors.toList()); + .toList(); return FrequencyData.of(allFrequencyData.getRsId(), wanted); } @@ -123,18 +127,25 @@ public PathogenicityData getVariantPathogenicityData(Variant variant, Set findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval) { - return null; + public Map findClinVarRecordsOverlappingInterval(@Nonnull GenomicInterval genomicInterval) { + return expectedClinVarData.entrySet().stream() + .filter(entry -> entry.getKey().overlapsWith(genomicInterval)) + .collect(Collectors.toUnmodifiableMap(Map.Entry::getKey, Map.Entry::getValue)); + } + + @Override + public GeneStatistics getGeneStatistics(@Nonnull String geneSymbol) { + return expectedGeneStats.getOrDefault(geneSymbol, GeneStatistics.builder(geneSymbol).build()); } public static Builder builder() { @@ -145,6 +156,8 @@ public static class Builder { private Set expectedWhiteList = new HashSet<>(); private Map expectedFrequencyData = new HashMap<>(); private Map expectedPathogenicityData = new HashMap<>(); + private Map expectedClinVarData = new HashMap<>(); + private Map expectedGeneStats = new HashMap<>(); public Builder expectedWhiteList(Set expectedWhiteList) { this.expectedWhiteList = expectedWhiteList; @@ -176,6 +189,26 @@ public Builder put(Variant variant, PathogenicityData expectedPathogenicityData) return this; } + public Builder expectedClinVarData(Map expectedClinVarData) { + this.expectedClinVarData = expectedClinVarData; + return this; + } + + public Builder put(Variant variant, ClinVarData clinVarData) { + this.expectedClinVarData.put(variant, clinVarData); + return this; + } + + public Builder expectedGeneStats(Map expectedGeneStats) { + this.expectedGeneStats = expectedGeneStats; + return this; + } + + public Builder put(GeneStatistics geneStatistics) { + this.expectedGeneStats.put(geneStatistics.geneSymbol(), geneStatistics); + return this; + } + public TestVariantDataService build() { return new TestVariantDataService(this); } @@ -213,6 +246,11 @@ public ClinVarData getClinVarData(GenomicVariant genomicVariant) { public Map findClinVarRecordsOverlappingInterval(GenomicInterval genomicInterval) { return Map.of(); } + + @Override + public GeneStatistics getGeneStatistics(@Nonnull String geneSymbol) { + return GeneStatistics.builder(geneSymbol).build(); + } } } diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImplTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImplTest.java index e8ff886ca..1d8febbd4 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImplTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/VariantDataServiceImplTest.java @@ -202,7 +202,7 @@ public void serviceQueryForSynonymousVariantReturnsEmptyPathogenicityData() { Mockito.when(defaultPathogenicityDao.getPathogenicityData(variant)).thenReturn(PathogenicityData.of(MutationTasterScore.of(1f))); Mockito.when(clinVarDao.getClinVarData(variant)).thenReturn(ClinVarData.empty()); PathogenicityData result = instance.getVariantPathogenicityData(variant, EnumSet.of(PathogenicitySource.MUTATION_TASTER)); - assertThat(result, equalTo(PathogenicityData.empty())); + assertThat(result, equalTo(PathogenicityData.of(MutationTasterScore.of(1f)))); } @Test diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStoreTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStoreTest.java index 7e55da727..5c99c114c 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStoreTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/genome/dao/ClinVarDaoMvStoreTest.java @@ -1,11 +1,13 @@ package org.monarchinitiative.exomiser.core.genome.dao; +import de.charite.compbio.jannovar.annotation.VariantEffect; import de.charite.compbio.jannovar.data.JannovarData; import de.charite.compbio.jannovar.mendel.ModeOfInheritance; import org.h2.mvstore.MVMap; import org.h2.mvstore.MVStore; import org.junit.jupiter.api.Disabled; import org.junit.jupiter.api.Test; +import org.monarchinitiative.exomiser.core.analysis.util.GeneConstraint; import org.monarchinitiative.exomiser.core.analysis.util.GeneConstraints; import org.monarchinitiative.exomiser.core.analysis.util.acmg.*; import org.monarchinitiative.exomiser.core.genome.GenomeAssembly; @@ -15,20 +17,24 @@ import org.monarchinitiative.exomiser.core.genome.jannovar.JannovarDataSourceLoader; import org.monarchinitiative.exomiser.core.model.*; import org.monarchinitiative.exomiser.core.model.frequency.FrequencyData; +import org.monarchinitiative.exomiser.core.model.frequency.FrequencySource; import org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData; import org.monarchinitiative.exomiser.core.model.pathogenicity.PathogenicityData; -import org.monarchinitiative.exomiser.core.model.pathogenicity.PathogenicityScore; import org.monarchinitiative.exomiser.core.model.pathogenicity.PathogenicitySource; +import org.monarchinitiative.exomiser.core.prioritisers.dao.DefaultDiseaseDao; +import org.monarchinitiative.exomiser.core.prioritisers.dao.DiseaseDao; +import org.monarchinitiative.exomiser.core.prioritisers.model.Disease; +import org.monarchinitiative.exomiser.core.prioritisers.model.InheritanceMode; import org.monarchinitiative.exomiser.core.proto.AlleleProto; import org.monarchinitiative.svart.*; import java.nio.file.Path; -import java.util.List; -import java.util.Map; -import java.util.Set; +import java.util.*; +import java.util.stream.Collectors; import static org.hamcrest.MatcherAssert.assertThat; import static org.hamcrest.Matchers.equalTo; +import static org.monarchinitiative.exomiser.core.model.pathogenicity.PathogenicitySource.*; class ClinVarDaoMvStoreTest { @@ -52,9 +58,8 @@ private AlleleProto.AlleleKey parseAlleleKey(String broadFormatVariant) { .build(); } - private GenomicVariant variant(String broadFormatVariant) { - String[] fields = broadFormatVariant.split("-"); - return GenomicVariant.of(GenomeAssembly.HG19.getContigByName(fields[0]), Strand.POSITIVE, Coordinates.ofAllele(CoordinateSystem.ONE_BASED, Integer.parseInt(fields[1]), fields[2]), fields[2], fields[3]); + private GenomicVariant variant(String variant) { + return parseVariant(GenomeAssembly.HG19, variant); } @Test @@ -79,6 +84,31 @@ void getClinVarData() { } } + @Test + void getClinVarDataNotReturningConflictingSig() { + try (MVStore mvStore = new MVStore.Builder().open()) { + var clinvarMap = MvStoreUtil.openClinVarMVMap(mvStore); + AlleleProto.AlleleKey alleleKey = parseAlleleKey("1-200-A-T"); + AlleleProto.ClinVar clinVar = AlleleProto.ClinVar.newBuilder() + .setVariationId("12345") + .setPrimaryInterpretation(AlleleProto.ClinVar.ClinSig.CONFLICTING_PATHOGENICITY_INTERPRETATIONS) + .setReviewStatus(AlleleProto.ClinVar.ReviewStatus.CRITERIA_PROVIDED_CONFLICTING_INTERPRETATIONS) + .putClinSigCounts("PATHOGENIC", 5) + .putClinSigCounts("UNCERTAIN_SIGNIFICANCE", 5) + .build(); + clinvarMap.put(alleleKey, clinVar); + + ClinVarDao instance = new ClinVarDaoMvStore(mvStore); + System.out.println("AlleleProtoAdaptor.toClinVarData: " + AlleleProtoAdaptor.toClinVarData(clinVar)); + GenomicVariant clinVarVariant = variant("1-200-A-T"); + System.out.println("ClinVarDao.getClinVarData: " + instance.getClinVarData(clinVarVariant)); + assertThat(instance.getClinVarData(clinVarVariant), equalTo(AlleleProtoAdaptor.toClinVarData(clinVar))); + + GenomicVariant nonClinVarVariant = variant("1-200-A-A"); + assertThat(instance.getClinVarData(nonClinVarVariant), equalTo(ClinVarData.empty())); + } + } + @Test void emptyStore() { ClinVarDaoMvStore clinVarDao = buildClinVarDaoMvStore(); @@ -217,14 +247,39 @@ void setPositionInButLengthIncorrectTest() { @Disabled("manual testing utility") @Test void manualDataExplorer() { - MVStore mvStore = new MVStore.Builder().fileName("/home/hhx640/Documents/exomiser-data/2402_hg19/2402_hg19_clinvar.mv.db").readOnly().open(); + // variant under assessment in 'Broad format' (i.e. hyphen seperated chr-pos-ref-alt) + String vua = "19-54123563-A-G"; // hg19-22-51019849-C-T possible cryptic splice variant? SPLICE_AI: 0.230 (PP3), ALPHA_MISSENSE: 0.125 + ModeOfInheritance modeOfInheritance = ModeOfInheritance.ANY; + // 37:10-124797364 // 38:10-123037848-G-A + 10-123051188-T-TAA + 10-123037804-C-A + // 10-89624227-A-G PTEN PATHOGENIC 3* START_LOST + // 10-89624245-G-T PTEN PATHOGENIC 2* STOP_GAINED + // 10-89624242-A-G PTEN PATHOGENIC 3* MISSENSE_VARIANT + + // 4-15589553-G-C - Hypothetical, not in ClinVar, LIKELY_PATHOGENIC [PVS1_Strong, PS1, PM2_Supporting] points=9? + // 1-63868019-G-A | 1-63877002-G-A + + // 2-232079571-G-A + // FP: + // MT-12706-T-C + // 11-6638385-C-T + // 12-103234252-T-C + + // 17-48275792-A-G SPLICE_DONOR_VARIANT (LP, ClinVar) + // 17-48275815-T-G SYNONYMOUS_VARIANT (VUS, ClinVar) + // + // 3'UTR hg38-20-58909654-A-G high spliceAI + GenomeAssembly assembly = GenomeAssembly.HG38; + + String dataDir = "/home/hhx640/Documents/exomiser-data/"; + String dataVersion = "2406_" + assembly; + + MVStore mvStore = new MVStore.Builder().fileName(dataDir + dataVersion + "/" + dataVersion + "_clinvar.mv.db").readOnly().open(); ClinVarDaoMvStore clinVarDao = new ClinVarDaoMvStore(mvStore); - MVStore alleleStore = new MVStore.Builder().fileName("/home/hhx640/Documents/exomiser-data/2402_hg19/2402_hg19_variants.mv.db").readOnly().open(); + MVStore alleleStore = new MVStore.Builder().fileName(dataDir + dataVersion + "/" + dataVersion + "_variants.mv.db").readOnly().open(); AllelePropertiesDao allelePropertiesDao = new AllelePropertiesDaoMvStore(alleleStore); - GenomeAssembly assembly = GenomeAssembly.HG19; - JannovarData jannovarData = JannovarDataSourceLoader.loadJannovarData(Path.of("/home/hhx640/Documents/exomiser-data/2402_hg19/2402_hg19_transcripts_ensembl.ser")); + JannovarData jannovarData = JannovarDataSourceLoader.loadJannovarData(Path.of(dataDir + dataVersion + "/" + dataVersion + "_transcripts_ensembl.ser")); VariantAnnotator variantAnnotator = new JannovarVariantAnnotator(assembly, jannovarData, ChromosomalRegionIndex.empty()); // 18-57550760-A-T NA // 18-57550753-A-C LP // 55217985 (hg19) @@ -237,8 +292,9 @@ void manualDataExplorer() { // https://mart.ensembl.org/info/genome/genebuild/canonical.html (see also vitt). Ideally the Jannovar Annotations // should be sorted before being converted to TranscriptAnnotations. This isn't an issue if MANE only // transcripts are being used as these are the only ones available to report on. - GenomicVariant genomicVariant = variant(assembly, "10-89624227-A-G"); // 10-123256215-T-G hg38:10-121496701-T-G + GenomicVariant genomicVariant = parseVariant(assembly, vua); // 10-123256215-T-G hg38:10-121496701-T-G + // hg38:4-25145092-C-T ENST00000382103.7(SEPSECS):c.846G>A (SEPSECS)p.(Leu282=) SpliceAI=0.42 // 10-89624227-A-G (PTEN) // 10-123247514-C-G : PS1, PM1, PM2_Supporting, PM5_Supporting, PP3, PP5_Strong // 10-123247517-T-G : PS1_Supporting, PM1, PM2_Supporting, PM5_Supporting, PP2, PP3 @@ -246,18 +302,14 @@ void manualDataExplorer() { AlleleProto.AlleleKey alleleKey = AlleleProtoAdaptor.toAlleleKey(genomicVariant); // encode as VariantKey (https://doi.org/10.1101/473744) == 8 bytes fixed size (long); // System.out.println("AlleleKey size (bytes): " + alleleKey.getSerializedSize()); // SNP = 13 bytes, 11 bases = 23 - System.out.println(); - - System.out.println(clinVarDao.getClinVarData(genomicVariant)); - Map clinVarRecordsOverlappingInterval = clinVarDao.findClinVarRecordsOverlappingInterval(genomicVariant.withPadding(25, 25)); - clinVarRecordsOverlappingInterval.forEach((variant, clinVarData) -> System.out.println(toBroad(variant) + " : " + clinVarData)); System.out.println(); + Set pathSources = EnumSet.of(REVEL, MVP, ALPHA_MISSENSE, SPLICE_AI, REMM); List variantAnnotations = variantAnnotator.annotate(genomicVariant); AlleleProto.AlleleProperties alleleProperties = allelePropertiesDao.getAlleleProperties(alleleKey, assembly); - FrequencyData frequencyData = AlleleProtoAdaptor.toFrequencyData(alleleProperties); + FrequencyData frequencyData = AlleleProtoAdaptor.toFrequencyData(alleleProperties).toBuilder().filterSources(FrequencySource.NON_FOUNDER_POPS).build(); PathogenicityData pathogenicityData = AlleleProtoAdaptor.toPathogenicityData(alleleProperties); - pathogenicityData = PathogenicityData.of(pathogenicityData.pathogenicityScores().stream().filter(score -> score.getSource() == PathogenicitySource.ALPHA_MISSENSE).toList()); + pathogenicityData = PathogenicityData.of(pathogenicityData.pathogenicityScores().stream().filter(score -> pathSources.contains(score.getSource())).toList()); ClinVarData clinVarData = clinVarDao.getClinVarData(genomicVariant); VariantAnnotation variantAnnotation = variantAnnotations.isEmpty() ? null : variantAnnotations.get(0); VariantEvaluation variantEvaluation = VariantEvaluation.builder() @@ -268,45 +320,84 @@ void manualDataExplorer() { .annotations(variantAnnotation.getTranscriptAnnotations()) .frequencyData(frequencyData) .pathogenicityData(PathogenicityData.of(clinVarData, pathogenicityData.pathogenicityScores())) - .compatibleInheritanceModes(Set.of(ModeOfInheritance.AUTOSOMAL_RECESSIVE)) +// .whiteListed() + .compatibleInheritanceModes(Set.of(modeOfInheritance)) .build(); TranscriptAnnotation transcriptAnnotation = variantAnnotation != null && variantAnnotation.hasTranscriptAnnotations() ? variantAnnotation.getTranscriptAnnotations().get(0) : null; - System.out.println(toBroad(genomicVariant) + (variantAnnotation == null ? "" : " " + variantAnnotation.getGeneSymbol() + (transcriptAnnotation == null ? "" : ":" + transcriptAnnotation.getHgvsCdna() + ":" + transcriptAnnotation.getHgvsProtein() ) + " " + variantAnnotation.getVariantEffect())); - System.out.println(frequencyData.getRsId() + " " + (transcriptAnnotation == null ? "" : transcriptAnnotation.getAccession())); + Set varEffects = variantAnnotation != null && variantAnnotation.hasTranscriptAnnotations() ? variantAnnotation.getTranscriptAnnotations().stream().map(TranscriptAnnotation::getVariantEffect).collect(Collectors.toUnmodifiableSet()) : Set.of(); + System.out.println(toBroad(genomicVariant) + " " + (frequencyData.getRsId().isEmpty() ? "-" : frequencyData.getRsId()) + " " + (variantAnnotation == null ? "" : variantAnnotation.getGeneSymbol() + (transcriptAnnotation == null ? "" : ":" + transcriptAnnotation.getAccession() + ":" + transcriptAnnotation.getHgvsCdna() + ":" + transcriptAnnotation.getHgvsProtein() + " " + transcriptAnnotation.getRankType() + " " + transcriptAnnotation.getRank() + "/" + transcriptAnnotation.getRankTotal()) + " " + varEffects)); String geneSymbol = variantAnnotation.getGeneSymbol(); - System.out.println(geneSymbol + " " + GeneConstraints.geneConstraint(geneSymbol)); - System.out.println(clinVarData.isEmpty() ? "" : clinVarData.getPrimaryInterpretation() + " (" + clinVarData.starRating() + "*) " + clinVarData.getVariationId() + " " + clinVarData.getGeneSymbol() + ":" + clinVarData.getHgvsCdna() + ":" + clinVarData.getHgvsProtein() + " " + clinVarData.getVariantEffect()); - System.out.println("Variant score: " + variantEvaluation.getVariantScore() + " Frequency score: " + variantEvaluation.getFrequencyScore() + " Pathogenicity score: " + variantEvaluation.getPathogenicityScore()); - System.out.println("Frequency data:"); + GeneConstraint geneConstraint = GeneConstraints.geneConstraint(geneSymbol); + if (geneConstraint != null) { + System.out.println(geneSymbol + " " + geneConstraint + (geneConstraint.isLossOfFunctionIntolerant() ? (" (LOF INTOLERANT)") : "")); + } + System.out.println("ClinVar: " + (clinVarData.isEmpty() ? "-" : formatClinVarData(clinVarData))); + System.out.println("Variant score: " + variantEvaluation.getVariantScore() + " Frequency score: " + variantEvaluation.getFrequencyScore() + " Pathogenicity score: " + variantEvaluation.getPathogenicityScore() + (variantEvaluation.isWhiteListed() ? " (WHITELIST VARIANT - all scores set to 1.0)" : "")); + System.out.println("Frequency score: " + frequencyData.frequencyScore()); if (frequencyData.isEmpty()) { - System.out.println("\n\t-"); + System.out.println("\t(no frequency data)"); } else { - System.out.println("\tfrequency score: " + frequencyData.frequencyScore()); - frequencyData.frequencies().forEach(freq -> System.out.println("\t" + freq.source() + "=" + freq.frequency() + "(" + freq.ac() + "|" + freq.an() + "|" + freq.homs() + ")")); + frequencyData.frequencies().forEach(freq -> System.out.println("\t" + freq.source() + "=" + freq.frequency() + (freq.an() == 0 ? "" : "(" + freq.ac() + "|" + freq.an() + "|" + freq.homs() + ")"))); } - System.out.println("Pathogenicity scores:"); + System.out.println("Pathogenicity score: " + pathogenicityData.pathogenicityScore()); if (pathogenicityData.isEmpty()) { - System.out.println("\t-"); + System.out.println("\t(no pathogenicity data)"); } else { - System.out.println("\tpathogenicity score: " + pathogenicityData.pathogenicityScore()); pathogenicityData.pathogenicityScores().forEach(path -> System.out.println("\t" + path)); } AcmgEvidenceAssigner acmgEvidenceAssigner = new Acmg2015EvidenceAssigner("sample", Pedigree.justProband("sample"), clinVarDao); - var acmgEvidence = acmgEvidenceAssigner.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_RECESSIVE, List.of(variantEvaluation), List.of(), List.of()); + Disease disease = Disease.builder().diseaseId("DISEASE:1").diseaseName("disease").inheritanceMode(InheritanceMode.AUTOSOMAL_RECESSIVE).build(); + AcmgEvidence acmgEvidence = acmgEvidenceAssigner.assignVariantAcmgEvidence(variantEvaluation, modeOfInheritance, List.of(variantEvaluation), List.of(disease), List.of()); AcmgEvidenceClassifier classifier = new Acmg2020PointsBasedClassifier(); // should use an AcmgAssignmentCalculator to figure out the correct disease-gene association to use - System.out.println(classifier.classify(acmgEvidence) + " " + acmgEvidence + " points=" + acmgEvidence.points()); + System.out.println(classifier.classify(acmgEvidence) + " " + acmgEvidence + " points=" + acmgEvidence.points() + " score=" + acmgEvidence.postProbPath()); + +// var manualEvidence = AcmgEvidence.builder() +// .add(AcmgCriterion.PM2, AcmgCriterion.Evidence.SUPPORTING) +// .add(AcmgCriterion.PP3, AcmgCriterion.Evidence.SUPPORTING) +// .add(AcmgCriterion.PS1) +// .build(); +// System.out.println(classifier.classify(manualEvidence) + " " + manualEvidence + " points=" + manualEvidence.points()); + + System.out.println(); + + GenomicRegion clinVarSearchInterval = genomicVariant.withPadding(25, 25); + String interval = clinVarSearchInterval.contig().name() + ":" + clinVarSearchInterval.startOneBased() + "-" + clinVarSearchInterval.end(); + System.out.println("ClinVar neighbourhood " + interval + " (" + genomicVariant.start() + " +/-25 bases):"); + Map clinVarRecordsOverlappingInterval = clinVarDao.findClinVarRecordsOverlappingInterval(clinVarSearchInterval); + clinVarRecordsOverlappingInterval.forEach((variant, data) -> System.out.println(toBroad(variant) + " : " + formatClinVarData(data))); + //TODO add known diseases + } + + private String formatClinVarData(ClinVarData clinVarData) { + return clinVarData.getPrimaryInterpretation() + (clinVarData.getPrimaryInterpretation() == ClinVarData.ClinSig.CONFLICTING_PATHOGENICITY_INTERPRETATIONS ? " " + clinVarData.getConflictingInterpretationCounts() : "") + " (" + clinVarData.starRating() + "*) " + clinVarData.getVariationId() + " " + clinVarData.getGeneSymbol() + ":" + clinVarData.getHgvsCdna() + ":" + clinVarData.getHgvsProtein() + " " + clinVarData.getVariantEffect() + " (" + clinVarData.getReviewStatus() + ")"; } private String toBroad(GenomicVariant genomicVariant) { return genomicVariant.contig().name() + '-' + genomicVariant.start() + '-' + genomicVariant.ref() + '-' + genomicVariant.alt(); } - private GenomicVariant variant(GenomeAssembly genomeAssembly, String broadFormatVariant) { - String[] fields = broadFormatVariant.split("-"); + /** + * Parses small sequence variants of the form `chr-pos-ref-alt`. For example: + * 
+     *     SNP  1-12345-A-T
+     *     SNP  1:12345:A:T
+     *     DEL  1-12345-AT-A
+     *     INS  1-12345-A-AT
+     *     MNV  1-12345-AT-GC
+     *     INV  1-12345-AT-TA
+     *
+ * Separators can be either hyphens '-' or colons ':'. The genomic assembly is also required. + * + * @param genomeAssembly Genomic assembly for the variant coordinates + * @param s The string representation of the variant + * @return A {@link GenomicVariant} + */ + private GenomicVariant parseVariant(GenomeAssembly genomeAssembly, String s) { + String[] fields = s.split("[-:]"); return GenomicVariant.of(genomeAssembly.getContigByName(fields[0]), Strand.POSITIVE, Coordinates.ofAllele(CoordinateSystem.ONE_BASED, Integer.parseInt(fields[1]), fields[2]), fields[2], fields[3]); } } \ No newline at end of file From 7621e7838269f605e58c9731fe014f1b58e25f7d Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Mon, 2 Sep 2024 10:28:47 +0100 Subject: [PATCH 10/21] Update Acmg2015EvidenceAssigner to include BS1, BS2 assignments. Refactor Acmg2015EvidenceAssigner missense assignment methods into new AcmgMissenseInFrameIndelEvidenceAssigner class. Add PP2/BP1 assignments to AcmgMissenseInFrameIndelEvidenceAssigner using GeneStatistics Update Exomiser version to 14.1.0-ALPHA --- exomiser-cli/pom.xml | 2 +- exomiser-core/pom.xml | 2 +- .../util/acmg/Acmg2015EvidenceAssigner.java | 363 +++-------------- ...gMissenseInFrameIndelEvidenceAssigner.java | 294 ++++++++++++++ .../util/acmg/AcmgPVS1EvidenceAssigner.java | 29 +- .../util/acmg/AcmgSpliceEvidenceAssigner.java | 59 ++- .../core/model/AlleleProtoAdaptor.java | 6 +- .../acmg/Acmg2015EvidenceAssignerTest.java | 378 +++++++++++++++--- .../acmg/AcmgAssignmentCalculatorTest.java | 4 +- exomiser-data-genome/pom.xml | 13 +- exomiser-data-phenotype/pom.xml | 2 +- exomiser-rest-prioritiser/pom.xml | 2 +- exomiser-spring-boot-autoconfigure/pom.xml | 2 +- exomiser-spring-boot-starter/pom.xml | 2 +- exomiser-spring-boot-test/pom.xml | 2 +- exomiser-web/pom.xml | 2 +- phenix-repository/pom.xml | 2 +- pom.xml | 8 +- 18 files changed, 771 insertions(+), 401 deletions(-) create mode 100644 exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgMissenseInFrameIndelEvidenceAssigner.java diff --git a/exomiser-cli/pom.xml b/exomiser-cli/pom.xml index 8dfbafcae..df24df4b5 100644 --- a/exomiser-cli/pom.xml +++ b/exomiser-cli/pom.xml @@ -32,7 +32,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA diff --git a/exomiser-core/pom.xml b/exomiser-core/pom.xml index 55135dc45..34a8844ca 100644 --- a/exomiser-core/pom.xml +++ b/exomiser-core/pom.xml @@ -30,7 +30,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java index 1963c95a1..167fcede4 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssigner.java @@ -22,31 +22,25 @@ import de.charite.compbio.jannovar.annotation.VariantEffect; import de.charite.compbio.jannovar.mendel.ModeOfInheritance; -import org.monarchinitiative.exomiser.core.analysis.util.GeneConstraint; -import org.monarchinitiative.exomiser.core.analysis.util.GeneConstraints; import org.monarchinitiative.exomiser.core.analysis.util.InheritanceModeAnalyser; import org.monarchinitiative.exomiser.core.genome.GenomeAssembly; import org.monarchinitiative.exomiser.core.genome.dao.ClinVarDao; import org.monarchinitiative.exomiser.core.model.*; import org.monarchinitiative.exomiser.core.model.Pedigree.Individual; +import org.monarchinitiative.exomiser.core.model.frequency.Frequency; import org.monarchinitiative.exomiser.core.model.frequency.FrequencyData; import org.monarchinitiative.exomiser.core.model.frequency.FrequencySource; import org.monarchinitiative.exomiser.core.model.pathogenicity.*; import org.monarchinitiative.exomiser.core.phenotype.ModelPhenotypeMatch; import org.monarchinitiative.exomiser.core.prioritisers.model.Disease; import org.monarchinitiative.exomiser.core.proto.AlleleProto; -import org.monarchinitiative.svart.*; import org.slf4j.Logger; import org.slf4j.LoggerFactory; import java.util.List; -import java.util.Map; import java.util.Objects; import java.util.Set; -import java.util.regex.Matcher; -import java.util.regex.Pattern; -import static de.charite.compbio.jannovar.annotation.VariantEffect.*; import static org.monarchinitiative.exomiser.core.analysis.util.acmg.AcmgCriterion.*; /** @@ -99,8 +93,6 @@ public class Acmg2015EvidenceAssigner implements AcmgEvidenceAssigner { AlleleProtoAdaptor.toAlleleKey(3, 15_645_186, "G", "C") ); - // e.g. p.(Lys567Thr) - private static final Pattern MISSENSE_HGVS_P = Pattern.compile("p\\.\\((?[A-Z][a-z]{2}\\d+)(?[A-Z][a-z]{2})\\)"); private final ClinVarDao clinVarDao; @@ -152,35 +144,31 @@ public AcmgEvidence assignVariantAcmgEvidence(VariantEvaluation variantEvaluatio // BA1 is supposed to be used as a filtering criterion where no other evidence need be considered. return acmgEvidenceBuilder.build(); } + // TODO: MT specific rules // PM2 "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium" assignPM2(acmgEvidenceBuilder, frequencyData, modeOfInheritance); - - - boolean hasCompatibleDiseaseMatches = !compatibleDiseaseMatches.isEmpty(); + // BS1 "Allele frequency is greater than expected for disorder" + assignBS1(acmgEvidenceBuilder, variantEvaluation, frequencyData, variantEvaluation.getPathogenicityData().clinVarData()); + // BS2 "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age" + assignBS2(acmgEvidenceBuilder, variantEvaluation, modeOfInheritance, knownDiseases, frequencyData, variantEvaluation.getPathogenicityData().clinVarData()); // PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" + // "Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion" https://doi.org/10.1002/humu.23626 AcmgPVS1EvidenceAssigner.assignPVS1(acmgEvidenceBuilder, variantEvaluation, probandSex, modeOfInheritance, knownDiseases); - // ignore non-missense, truncating, splice or mitochondrial variants - if (isMissenseOrInframeIndel(variantEvaluation.getVariantEffect()) && variantEvaluation.contigId() != 25) { - // ensure region is within contig bounds - Contig contig = variantEvaluation.contig(); - var upStream = Math.max(1, variantEvaluation.start() - 25); - var downStream = Math.min(contig.length(), variantEvaluation.start() + 25); - GenomicInterval genomicInterval = GenomicInterval.of(contig, Strand.POSITIVE, Coordinates.oneBased(upStream, downStream)); - var localClinVarData = clinVarDao.findClinVarRecordsOverlappingInterval(genomicInterval); - // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" - // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" - assignPS1PM5(acmgEvidenceBuilder, variantEvaluation, localClinVarData); - // PM1 "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation" - assignPM1(acmgEvidenceBuilder, variantEvaluation, localClinVarData); - // TODO: PM1/BP3 "In-frame deletions/insertions in a repetitive region without a known function" - requires domain information. - } + // Apply PS1, PM5, PM1 to missense and inframe indels + AcmgMissenseInFrameIndelEvidenceAssigner.assignMissenseEvidence(acmgEvidenceBuilder, variantEvaluation, modeOfInheritance, knownDiseases, clinVarDao); + + // TODO: MISSENSE_VARIANT should be assessed for splicing score if they are also a SPLICE_REGION_VARIANT then the max of these two outcomes should be used. + // Note that these can conflict e.g. a MISSENSE with a low REVEL score can have a BP4 assigned yet have a SPLICE_AI > 0.2 and therefore a PP3 if assessed + // as a SPLICE_REGION_VARIANT. This could also effect the PS1 assignment if a splice variant has been assigned a PP3 and there are other CLinVar variants in the region. + // e.g. 22-51019849-C-T missense_variant|splice_region_variant MODERATE NC_000022.10:g.51019849C>T ENST00000406938.2(CHKB):c.581G>A (CHKB)p.(Arg194Gln) 1638bp 395aa // apply PVS1, PS1, PP3, BP4, BP7 to splice region variants according to "Using the ACMG/AMP framework to capture // evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup" // https://doi.org/10.1016/j.ajhg.2023.06.002 AcmgSpliceEvidenceAssigner.assignSpliceEvidence(acmgEvidenceBuilder, variantEvaluation, modeOfInheritance, knownDiseases, clinVarDao); + boolean hasCompatibleDiseaseMatches = !compatibleDiseaseMatches.isEmpty(); if (pedigree.containsId(probandId)) { Individual proband = pedigree.getIndividualById(probandId); // PS2 "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history" @@ -199,7 +187,6 @@ public AcmgEvidence assignVariantAcmgEvidence(VariantEvaluation variantEvaluatio // PP4 "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology" assignPP4(acmgEvidenceBuilder, compatibleDiseaseMatches); - PathogenicityData pathogenicityData = variantEvaluation.getPathogenicityData(); ClinVarData clinVarData = variantEvaluation.getPathogenicityData().clinVarData(); if (!clinVarData.isEmpty()) { // PP5 "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation" @@ -207,96 +194,46 @@ public AcmgEvidence assignVariantAcmgEvidence(VariantEvaluation variantEvaluatio // BP6 "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation" assignBP6(acmgEvidenceBuilder, clinVarData); } - // PP3 "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)" - // BP4 "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)" - // TODO: internalise in PathogenicityData and create proper cutoff values adding isPath/isbenign to PathogenicityScore - assignPP3orBP4(acmgEvidenceBuilder, pathogenicityData); return acmgEvidenceBuilder.build(); } -// /** -// * PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" -// */ -// private void assignPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List knownDiseases) { -// // TODO: add new method - gene.getAssociatedDiseases() -// // also need ClinvarCache.getClinvarDataForGene(GeneIdentifier geneIdentifier) -// -// // Certain types of variants (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon or multiexon -// // deletion) can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of tran- -// // scription or nonsense-mediated decay of an altered transcript. One must, however, exercise caution when classifying these -// // variants as pathogenic by considering the following principles: -// // (i) When classifying such variants as pathogenic, one must ensure that null variants are a known mechanism of -// // pathogenicity consistent with the established inheritance pattern for the disease. For example, there are genes for -// // which only heterozygous missense variants cause disease and null variants are benign in a heterozygous state (e.g., -// // many hypertrophic cardiomyopathy genes). A novel heterozygous nonsense variant in the MYH7 gene would -// // not be considered pathogenic for dominant hypertrophic cardiomyopathy based solely on this evidence, whereas a -// // novel heterozygous nonsense variant in the CFTR gene would likely be considered a recessive pathogenic variant. -// // Caveats: -// // • Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7) -// // • Use caution interpreting LOF variants at the extreme 3′ end of a gene -// // • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact -// // • Use caution in the presence of multiple transcripts -// -// GeneConstraint geneContraint = GeneConstraints.geneConstraint(variantEvaluation.getGeneSymbol()); -// // Should this be using the hasCompatibleDiseaseMatches variable? -// boolean inGeneWithKnownDiseaseAssociations = !knownDiseases.isEmpty(); -// if (inGeneWithKnownDiseaseAssociations && isLossOfFunctionEffect(variantEvaluation.getVariantEffect()) -// && (modeOfInheritance == ModeOfInheritance.ANY -// || compatibleWithRecessive(modeOfInheritance) -// || compatibleWithDominant(modeOfInheritance) && (geneContraint != null && geneContraint.isLossOfFunctionIntolerant()) -// ) -// ) { -// if (variantEvaluation.hasTranscriptAnnotations()) { -// TranscriptAnnotation transcriptAnnotation = variantEvaluation.getTranscriptAnnotations().get(0); -// if (predictedToLeadToNmd(transcriptAnnotation)) { -// acmgEvidenceBuilder.add(PVS1); -// } else { -// // Not predicted to lead to NMD? Downgrade to STRONG -// acmgEvidenceBuilder.add(PVS1, Evidence.STRONG); -// } -// } else { -// // shouldn't happen that there are no transcript annotations, but just in case... -// acmgEvidenceBuilder.add(PVS1, Evidence.STRONG); -// } -// } -// } -// -// private boolean isLossOfFunctionEffect(VariantEffect variantEffect) { -// return variantEffect == VariantEffect.START_LOST -// || variantEffect == VariantEffect.STOP_LOST -// || variantEffect == VariantEffect.STOP_GAINED -// || variantEffect == VariantEffect.FRAMESHIFT_ELONGATION -// || variantEffect == VariantEffect.FRAMESHIFT_TRUNCATION -// || variantEffect == VariantEffect.FRAMESHIFT_VARIANT -// || variantEffect == VariantEffect.SPLICE_ACCEPTOR_VARIANT -// || variantEffect == VariantEffect.SPLICE_DONOR_VARIANT -// || variantEffect == VariantEffect.EXON_LOSS_VARIANT; -// } -// -// private boolean predictedToLeadToNmd(TranscriptAnnotation transcriptAnnotation) { -// // predicted to lead to NMD if in last exon or last 50bp of penultimate exon, or in single exon transcript -// boolean notInLastExon = transcriptAnnotation.getRank() < transcriptAnnotation.getRankTotal(); -// boolean isSingleExonTranscript = transcriptAnnotation.getRankTotal() == 1; -// return transcriptAnnotation.getRankType() == TranscriptAnnotation.RankType.EXON && (notInLastExon || isSingleExonTranscript); -// } -// -// private boolean compatibleWithRecessive(ModeOfInheritance modeOfInheritance) { -// if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_RECESSIVE) { -// return true; -// } -// return probandSex == Individual.Sex.FEMALE && modeOfInheritance == ModeOfInheritance.X_RECESSIVE; -// } -// -// private boolean compatibleWithDominant(ModeOfInheritance modeOfInheritance) { -// if (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_DOMINANT) { -// return true; -// } -// if (probandSex == Individual.Sex.MALE && (modeOfInheritance == ModeOfInheritance.X_RECESSIVE || modeOfInheritance == ModeOfInheritance.X_DOMINANT)) { -// return true; -// } -// return (probandSex == Individual.Sex.FEMALE || probandSex == Individual.Sex.UNKNOWN) && modeOfInheritance == ModeOfInheritance.X_DOMINANT; -// } + private void assignBS1(AcmgEvidence.Builder acmgEvidenceBuilder, Variant variant, FrequencyData frequencyData, ClinVarData clinVarData) { + boolean isReportedPorLP = clinVarData.starRating() >= 1 && isPathOrLikelyPath(clinVarData.getPrimaryInterpretation()); + if ((acmgEvidenceBuilder.contains(BA1) || acmgEvidenceBuilder.contains(PM2)) && !isReportedPorLP) { + float maxNonFounderPopFreq = frequencyData.maxFreqForPopulation(FrequencySource.NON_FOUNDER_POPS); + if (variant.contigId() == 25 && maxNonFounderPopFreq > 0.5) { + // hard cutoff for MT based on AMP/ACMG "Specifications of the ACMG/AMP standards and guidelines + //for mitochondrial DNA variant interpretation" doi:10.1002/humu.24107 + acmgEvidenceBuilder.add(BS1); + } else if (maxNonFounderPopFreq > 1.5) { + // InterVar uses a cutoff of 1% but this is half our default max for AR filtering (2%). More empirical + // gene-specific cut-offs can be generated from the max frequencies seen for the most common P/LP clinvar + // variant - i.e. GeneStats required + acmgEvidenceBuilder.add(BS1); + } + } + } + + // BS2 "Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age" + private void assignBS2(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List diseases, FrequencyData frequencyData, ClinVarData clinVarData) { + // TODO: need GENE MOI + //We first determine the mode of inheritance of the gene, then compares the allele count (see allele frequency for quality checks) to the corresponding threshold: + // + // recessive or X-linked genes: allele count greater than 2, + // dominant genes: allele count greater than 5. + // + //Rule BS2 is not evaluated if rule BA1 was triggered, to avoid double-counting the same evidence, and for performance we disable BS2 if rule PM2 triggered. + int alleleCount = frequencyData.frequencies().stream().filter(frequency -> FrequencySource.NON_FOUNDER_POPS.contains(frequency.source())).mapToInt(Frequency::homs).sum(); + if (!(acmgEvidenceBuilder.contains(BA1) || acmgEvidenceBuilder.contains(PM2))) { + if (alleleCount > 2 && (modeOfInheritance == ModeOfInheritance.AUTOSOMAL_RECESSIVE || modeOfInheritance == ModeOfInheritance.X_RECESSIVE || modeOfInheritance == ModeOfInheritance.X_DOMINANT)) { + acmgEvidenceBuilder.add(BS2); + } + if (alleleCount > 5 && modeOfInheritance == ModeOfInheritance.AUTOSOMAL_DOMINANT) { + acmgEvidenceBuilder.add(BS2); + } + } + } /** * PM3 "For recessive disorders, detected in trans with a pathogenic variant" @@ -348,101 +285,12 @@ private boolean inCis(SampleGenotype thisVariantGenotype, SampleGenotype otherVa && thisVariantGenotype.equals(otherVariantGenotype); } - - // PM1 "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation" - private void assignPM1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Map localClinVarData) { - // TODO - need UniProt domain / site info and clinvar counts - // can upgrade to STRONG - // https://www.cell.com/ajhg/fulltext/S0002-9297(22)00461-X suggests to limit the combined evidence from PM1 and PP3 to strong - int pathCount = 0; - int vusCount = 0; - int benignCount = 0; - for (var entry : localClinVarData.entrySet()) { - ClinVarData clinVarData = entry.getValue(); - ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); - if (isMissenseOrInframeIndel(clinVarData.getVariantEffect())) { - if (isPathOrLikelyPath(primaryInterpretation)) { - pathCount++; - } - if (primaryInterpretation == ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) { - vusCount++; - } - if (isBenignOrLikelyBenign(primaryInterpretation)) { - benignCount++; - } - } - } - logger.debug("PM1 evidence for region {} {}:{}-{} Paths: {} VUSs: {} Benigns: {}", variantEvaluation.getGenomeAssembly(), variantEvaluation.contigId(), variantEvaluation.start() - 25, variantEvaluation.end() + 25, pathCount, vusCount, benignCount); - if (pathCount >= 4 && benignCount == 0) { - // could do funkier thing to score other path variants by severity/star rating and distance to variant - if (pathCount > vusCount) { - acmgEvidenceBuilder.add(PM1); - logger.debug("{} -> {}", variantEvaluation, PM1); - } else { - acmgEvidenceBuilder.add(PM1, Evidence.SUPPORTING); - logger.debug("{} -> {}_Supporting", variantEvaluation, PM1); - } - } - } - - // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" - // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" - private void assignPS1PM5(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Map localClinVarData) { - if (variantEvaluation.getTranscriptAnnotations().isEmpty()) { - return; - } - String variantProteinChange = variantEvaluation.getTranscriptAnnotations().get(0).getHgvsProtein(); - Matcher queryVariantMatcher = MISSENSE_HGVS_P.matcher(variantProteinChange); - boolean matches = queryVariantMatcher.matches(); - String aaRefPos = matches ? queryVariantMatcher.group("refPos") : ""; - String aaAlt = matches ? queryVariantMatcher.group("alt") : ""; - for (var entry : localClinVarData.entrySet()) { - ClinVarData clinVarData = entry.getValue(); - ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); - if (isMissenseOrInframeIndel(clinVarData.getVariantEffect()) && isPathOrLikelyPath(primaryInterpretation)) { - GenomicVariant clinVarVariant = entry.getKey(); - if (Math.abs(clinVarVariant.distanceTo(variantEvaluation)) <= 2 && GenomicVariant.compare(clinVarVariant, variantEvaluation) != 0) { - // within codon so check for same AA change or different AA change - Matcher clinvarMatcher = MISSENSE_HGVS_P.matcher(clinVarData.getHgvsProtein()); - if (clinvarMatcher.matches()) { - String clnAaRefPos = clinvarMatcher.group("refPos"); - String clnAaAlt = clinvarMatcher.group("alt"); - if (aaRefPos.equals(clnAaRefPos)) { - if (aaAlt.equals(clnAaAlt)) { - // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" - Evidence evidence; - if (clinVarData.starRating() >= 2) { - evidence = Evidence.STRONG; - } else if (clinVarData.starRating() == 1) { - evidence = Evidence.MODERATE; - } else { - evidence = Evidence.SUPPORTING; - } - logger.debug("{} -> {}_{}", clinVarData.getHgvsProtein(), PS1, evidence); - acmgEvidenceBuilder.add(PS1, evidence); - } else { - Evidence evidence = clinVarData.starRating() >= 2 ? Evidence.MODERATE : Evidence.SUPPORTING; - logger.debug("{} -> {}_{}", clinVarData.getHgvsProtein(), PM5, evidence); - // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" - acmgEvidenceBuilder.add(PM5, evidence); - } - } - } - } - } - } - } - - private boolean isMissenseOrInframeIndel(VariantEffect variantEffect) { - return variantEffect == VariantEffect.MISSENSE_VARIANT || variantEffect == VariantEffect.INFRAME_DELETION || variantEffect == VariantEffect.INFRAME_INSERTION; - } - /** * PP5 "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation" */ private void assignPP5(AcmgEvidence.Builder acmgEvidenceBuilder, ClinVarData clinVarData) { // avoid double-counting by not assigning if PS1 already assigned - if (acmgEvidenceBuilder.contains(PS1)) { + if (acmgEvidenceBuilder.contains(PS1)) { return; } ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); @@ -471,8 +319,11 @@ private void assignBP6(AcmgEvidence.Builder acmgEvidenceBuilder, ClinVarData cli boolean benignOrLikelyBenign = isBenignOrLikelyBenign(primaryInterpretation); if (benignOrLikelyBenign && clinVarData.starRating() == 1) { acmgEvidenceBuilder.add(BP6); - } else if (benignOrLikelyBenign && clinVarData.starRating() >= 2) { + } else if (benignOrLikelyBenign && clinVarData.starRating() == 2) { acmgEvidenceBuilder.add(BP6, Evidence.STRONG); + } else if (benignOrLikelyBenign && clinVarData.starRating() >= 3) { + // expert panel or practice guidelines + acmgEvidenceBuilder.add(BP6, Evidence.VERY_STRONG); } } @@ -529,8 +380,8 @@ private boolean possibleDeNovo(SampleGenotype ancestorGenotype, SampleGenotype p private void assignPM2(AcmgEvidence.Builder acmgEvidenceBuilder, FrequencyData frequencyData, ModeOfInheritance modeOfInheritance) { // allow local frequency occurrences as these are unverifiable as to their size or content. Also do not use isRepresentedInDatabase() // as this will exclude anything with an rsID which could be a ClinVar variant not seen in any population database. - boolean absentFromDatabase = frequencyData.isEmpty() || (frequencyData.size() == 1 && frequencyData.containsFrequencySource(FrequencySource.LOCAL)); - boolean atVeryLowFrequencyIfRecessive = modeOfInheritance.isRecessive() && frequencyData.maxFreqForPopulation(FrequencySource.NON_FOUNDER_POPS) < 0.01f; + boolean absentFromDatabase = frequencyData.maxFreq() == 0f || (frequencyData.size() == 1 && frequencyData.containsFrequencySource(FrequencySource.LOCAL)); + boolean atVeryLowFrequencyIfRecessive = (modeOfInheritance.isRecessive() || modeOfInheritance == ModeOfInheritance.ANY) && frequencyData.maxFreqForPopulation(FrequencySource.NON_FOUNDER_POPS) < 0.01f; if (absentFromDatabase || atVeryLowFrequencyIfRecessive) { acmgEvidenceBuilder.add(PM2, Evidence.SUPPORTING); } @@ -569,102 +420,6 @@ private void assignPM6(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluati } } - /** - * PP3 "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)" - * BP4 "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)" - */ - private void assignPP3orBP4(AcmgEvidence.Builder acmgEvidenceBuilder, PathogenicityData pathogenicityData) { - // These approaches are broadly similar in recommending just using one predictor and REVEL is consistently - // seen to out-perform other predictors. In our testing we also found that the REVEL-only approach worked best. - - // updated from "Evidence-based calibration of computational tools for missense variant pathogenicity - // classification and ClinGen recommendations for clinical use of PP3/BP4 criteria" - // https://www.biorxiv.org/content/10.1101/2022.03.17.484479v1 - // - var revelScore = pathogenicityData.pathogenicityScore(PathogenicitySource.REVEL); - if (revelScore != null) { - assignRevelBasedPP3BP4Classification(acmgEvidenceBuilder, revelScore); - } else { - // See "Assessing performance of pathogenicity predictors using clinically relevant variant datasets" - // http://dx.doi.org/10.1136/jmedgenet-2020-107003 - assignEnsembleBasedPP3BP4Classification(acmgEvidenceBuilder, pathogenicityData); - } - } - - /* - * Updated classification from "Evidence-based calibration of computational tools for missense variant pathogenicity - * classification and ClinGen recommendations for clinical use of PP3/BP4 criteria" - * https://www.biorxiv.org/content/10.1101/2022.03.17.484479v1 - * - * This method provided much better - */ - private void assignRevelBasedPP3BP4Classification(AcmgEvidence.Builder acmgEvidenceBuilder, PathogenicityScore revelScore) { - var revel = revelScore.getRawScore(); - // Taken from table 2 of https://www.biorxiv.org/content/10.1101/2022.03.17.484479v1 - // P_Strong P_Moderate P_Supporting B_Supporting B_Moderate B_Strong B_Very Strong - // ≥ 0.932 [0.773, 0.932) [0.644, 0.773) (0.183, 0.290] (0.016, 0.183] (0.003, 0.016] ≤ 0.003 - // PATHOGENIC categories - - if (revel >= 0.932f) { - acmgEvidenceBuilder.add(PP3, Evidence.STRONG); - } else if (revel < 0.932f && revel >= 0.773f) { - acmgEvidenceBuilder.add(PP3, Evidence.MODERATE); - } else if (revel < 0.773f && revel >= 0.644f) { - acmgEvidenceBuilder.add(PP3, Evidence.SUPPORTING); - } - // BENIGN categories - else if (revel > 0.183f && revel <= 0.290f) { - acmgEvidenceBuilder.add(BP4, Evidence.SUPPORTING); - } else if (revel > 0.016f && revel <= 0.183f) { - acmgEvidenceBuilder.add(BP4, Evidence.MODERATE); - } else if (revel > 0.003f && revel <= 0.016f) { - acmgEvidenceBuilder.add(BP4, Evidence.STRONG); - } else if (revel <= 0.003f) { - acmgEvidenceBuilder.add(BP4, Evidence.VERY_STRONG); - } - } - - /* - * Ensemble-based approach suggested in - * See "Assessing performance of pathogenicity predictors using clinically relevant variant datasets" - * http://dx.doi.org/10.1136/jmedgenet-2020-107003 - */ - private void assignEnsembleBasedPP3BP4Classification(AcmgEvidence.Builder acmgEvidenceBuilder, PathogenicityData pathogenicityData) { - int numBenign = 0; - int numPathogenic = 0; - List pathogenicityScores = pathogenicityData.pathogenicityScores(); - for (PathogenicityScore pathogenicityScore : pathogenicityScores) { - if (isPathogenic(pathogenicityScore)) { - numPathogenic++; - } else { - numBenign++; - } - } - if (pathogenicityScores.size() > 1 && numPathogenic > numBenign) { - acmgEvidenceBuilder.add(PP3); - } - if (pathogenicityScores.size() > 1 && numBenign > numPathogenic) { - acmgEvidenceBuilder.add(BP4); - } - } - - private boolean isPathogenic(PathogenicityScore pathogenicityScore) { - if (pathogenicityScore instanceof SiftScore score) { - return score.getRawScore() < SiftScore.SIFT_THRESHOLD; - } - if (pathogenicityScore instanceof MutationTasterScore score) { - return score.getScore() > MutationTasterScore.MTASTER_THRESHOLD; - } - if (pathogenicityScore instanceof PolyPhenScore score) { - return score.getScore() > PolyPhenScore.POLYPHEN_PROB_DAMAGING_THRESHOLD; - } - if (pathogenicityScore instanceof CaddScore score) { - // 95-99% most deleterious. - return score.getRawScore() >= 13.0f; - } - return pathogenicityScore.getScore() > 0.5f; - } - /** * PP4 "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology" */ @@ -675,7 +430,7 @@ private void assignPP4(AcmgEvidence.Builder acmgEvidenceBuilder, List= 0.7f) { acmgEvidenceBuilder.add(PP4, Evidence.MODERATE); - } else if (humanGenePhenotypeScoreForMoi < 0.7f && humanGenePhenotypeScoreForMoi >= 0.51) { + } else if (humanGenePhenotypeScoreForMoi < 0.7f && humanGenePhenotypeScoreForMoi >= 0.51f) { acmgEvidenceBuilder.add(PP4, Evidence.SUPPORTING); } } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgMissenseInFrameIndelEvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgMissenseInFrameIndelEvidenceAssigner.java new file mode 100644 index 000000000..2f3b436b6 --- /dev/null +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgMissenseInFrameIndelEvidenceAssigner.java @@ -0,0 +1,294 @@ +package org.monarchinitiative.exomiser.core.analysis.util.acmg; + +import de.charite.compbio.jannovar.annotation.VariantEffect; +import de.charite.compbio.jannovar.mendel.ModeOfInheritance; +import org.monarchinitiative.exomiser.core.genome.dao.ClinVarDao; +import org.monarchinitiative.exomiser.core.model.GeneStatistics; +import org.monarchinitiative.exomiser.core.model.VariantEvaluation; +import org.monarchinitiative.exomiser.core.model.pathogenicity.*; +import org.monarchinitiative.exomiser.core.prioritisers.model.Disease; +import org.monarchinitiative.svart.*; +import org.slf4j.Logger; +import org.slf4j.LoggerFactory; + +import java.util.List; +import java.util.Map; +import java.util.regex.Matcher; +import java.util.regex.Pattern; + +import static org.monarchinitiative.exomiser.core.analysis.util.acmg.AcmgCriterion.*; + +class AcmgMissenseInFrameIndelEvidenceAssigner { + + private static final Logger logger = LoggerFactory.getLogger(AcmgMissenseInFrameIndelEvidenceAssigner.class); + + // e.g. p.(Lys567Thr) + private static final Pattern MISSENSE_HGVS_P = Pattern.compile("p\\.\\((?[A-Z][a-z]{2}\\d+)(?[A-Z][a-z]{2})\\)"); + + private AcmgMissenseInFrameIndelEvidenceAssigner() { + // static utility class + } + + static void assignMissenseEvidence(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List knownDiseases, ClinVarDao clinVarDao) { + // ignore non-missense, truncating, splice or mitochondrial variants + if (isMissenseOrInframeIndel(variantEvaluation.getVariantEffect()) && variantEvaluation.contigId() != 25) { + // ensure region is within contig bounds + Contig contig = variantEvaluation.contig(); + var upStream = Math.max(1, variantEvaluation.start() - 25); + var downStream = Math.min(contig.length(), variantEvaluation.start() + 25); + GenomicInterval genomicInterval = GenomicInterval.of(contig, Strand.POSITIVE, Coordinates.oneBased(upStream, downStream)); + var localClinVarData = clinVarDao.findClinVarRecordsOverlappingInterval(genomicInterval); + // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" + // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" + assignPS1PM5(acmgEvidenceBuilder, variantEvaluation, localClinVarData); + // PM1 "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation" + assignPM1(acmgEvidenceBuilder, variantEvaluation, localClinVarData); + // TODO: BP3 "In-frame deletions/insertions in a repetitive region without a known function" - requires domain information. + + // PP2 "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease." + // BP1 "Missense variant in a gene for which primarily truncating variants are known to cause disease." + assignPP2orBP1(acmgEvidenceBuilder, variantEvaluation, clinVarDao); + // PP3 "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)" + // BP4 "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)" + assignPP3orBP4(acmgEvidenceBuilder, variantEvaluation.getPathogenicityData()); + } + } + + // PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. + // BP1 - Missense variant in a gene for which primarily truncating variants are known to cause disease. + private static void assignPP2orBP1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ClinVarDao clinVarDao) { + GeneStatistics geneStatistics = clinVarDao.getGeneStatistics(variantEvaluation.getGeneSymbol()); + boolean missenseOrInframeIndel = isMissenseOrInframeIndel(variantEvaluation.getVariantEffect()); + if (missenseOrInframeIndel && isPP2Gene(geneStatistics)) { + acmgEvidenceBuilder.add(PP2); + } else if (missenseOrInframeIndel && isBP1Gene(geneStatistics)) { + acmgEvidenceBuilder.add(BP1); + } + } + + // a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. + private static boolean isPP2Gene(GeneStatistics geneStatistics) { + int missensePathCount = geneStatistics.missensePathCount(); + int missenseVusCount = geneStatistics.missenseVusCount(); + int missenseBenignCount = geneStatistics.missenseBenignCount(); + return missensePathCount / (float) geneStatistics.pathCount() >= 0.75 && (missensePathCount / (float) missenseBenignCount >= 0.9) && ((float) missenseBenignCount / (missenseBenignCount + missenseVusCount + missensePathCount) <= 0.05); + } + + // a gene for which primarily truncating variants are known to cause disease. + private static boolean isBP1Gene(GeneStatistics geneStatistics) { + return geneStatistics.lofPathCount() / (float) geneStatistics.pathCount() >= 0.75; + } + + // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" + // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" + private static void assignPS1PM5(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Map localClinVarData) { + if (variantEvaluation.getTranscriptAnnotations().isEmpty()) { + return; + } + String variantProteinChange = variantEvaluation.getTranscriptAnnotations().get(0).getHgvsProtein(); + Matcher queryVariantMatcher = MISSENSE_HGVS_P.matcher(variantProteinChange); + boolean matches = queryVariantMatcher.matches(); + String aaRefPos = matches ? queryVariantMatcher.group("refPos") : ""; + String aaAlt = matches ? queryVariantMatcher.group("alt") : ""; + for (var entry : localClinVarData.entrySet()) { + ClinVarData clinVarData = entry.getValue(); + ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); + if (isMissenseOrInframeIndel(clinVarData.getVariantEffect()) && isPathOrLikelyPath(primaryInterpretation)) { + GenomicVariant clinVarVariant = entry.getKey(); + if (Math.abs(clinVarVariant.distanceTo(variantEvaluation)) <= 2 && GenomicVariant.compare(clinVarVariant, variantEvaluation) != 0) { + // within codon so check for same AA change or different AA change + Matcher clinvarMatcher = MISSENSE_HGVS_P.matcher(clinVarData.getHgvsProtein()); + if (clinvarMatcher.matches()) { + String clnAaRefPos = clinvarMatcher.group("refPos"); + String clnAaAlt = clinvarMatcher.group("alt"); + if (aaRefPos.equals(clnAaRefPos)) { + if (aaAlt.equals(clnAaAlt)) { + // PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" + AcmgCriterion.Evidence evidence; + if (clinVarData.starRating() >= 2) { + evidence = AcmgCriterion.Evidence.STRONG; + } else if (clinVarData.starRating() == 1) { + evidence = AcmgCriterion.Evidence.MODERATE; + } else { + evidence = AcmgCriterion.Evidence.SUPPORTING; + } + logger.debug("{} -> {}_{}", clinVarData.getHgvsProtein(), PS1, evidence); + acmgEvidenceBuilder.add(PS1, evidence); + } else { + AcmgCriterion.Evidence evidence = clinVarData.starRating() >= 2 ? AcmgCriterion.Evidence.MODERATE : AcmgCriterion.Evidence.SUPPORTING; + logger.debug("{} -> {}_{}", clinVarData.getHgvsProtein(), PM5, evidence); + // PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" + acmgEvidenceBuilder.add(PM5, evidence); + } + } + } + } + } + } + } + + // PM1 "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation" + private static void assignPM1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Map localClinVarData) { + // TODO - need UniProt domain / site info and clinvar counts + // can upgrade to STRONG + // https://www.cell.com/ajhg/fulltext/S0002-9297(22)00461-X suggests to limit the combined evidence from PM1 and PP3 to strong + int pathCount = 0; + int vusCount = 0; + int benignCount = 0; + for (var entry : localClinVarData.entrySet()) { + ClinVarData clinVarData = entry.getValue(); + ClinVarData.ClinSig primaryInterpretation = clinVarData.getPrimaryInterpretation(); + if (isMissenseOrInframeIndel(clinVarData.getVariantEffect())) { + if (isPathOrLikelyPath(primaryInterpretation)) { + pathCount++; + } + if (primaryInterpretation == ClinVarData.ClinSig.UNCERTAIN_SIGNIFICANCE) { + vusCount++; + } + if (isBenignOrLikelyBenign(primaryInterpretation)) { + benignCount++; + } + } + } + logger.debug("PM1 evidence for region {} {}:{}-{} Paths: {} VUSs: {} Benigns: {}", variantEvaluation.getGenomeAssembly(), variantEvaluation.contigId(), variantEvaluation.start() - 25, variantEvaluation.end() + 25, pathCount, vusCount, benignCount); + if (pathCount >= 4 && benignCount == 0) { + // could do funkier thing to score other path variants by severity/star rating and distance to variant + if (pathCount > vusCount) { + acmgEvidenceBuilder.add(PM1); + logger.debug("{} -> {}", variantEvaluation, PM1); + } else { + acmgEvidenceBuilder.add(PM1, Evidence.SUPPORTING); + logger.debug("{} -> {}_Supporting", variantEvaluation, PM1); + } + } + } + + private static boolean isMissenseOrInframeIndel(VariantEffect variantEffect) { + return variantEffect == VariantEffect.MISSENSE_VARIANT || variantEffect == VariantEffect.INFRAME_DELETION || variantEffect == VariantEffect.INFRAME_INSERTION; + } + + private static boolean isBenignOrLikelyBenign(ClinVarData.ClinSig clinSig) { + return clinSig == ClinVarData.ClinSig.BENIGN || clinSig == ClinVarData.ClinSig.LIKELY_BENIGN || clinSig == ClinVarData.ClinSig.BENIGN_OR_LIKELY_BENIGN; + } + + private static boolean isPathOrLikelyPath(ClinVarData.ClinSig clinSig) { + return clinSig == ClinVarData.ClinSig.PATHOGENIC || clinSig == ClinVarData.ClinSig.LIKELY_PATHOGENIC || clinSig == ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC; + } + + + /** + * PP3 "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)" + * BP4 "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)" + */ + private static void assignPP3orBP4(AcmgEvidence.Builder acmgEvidenceBuilder, PathogenicityData pathogenicityData) { + // These approaches are broadly similar in recommending just using one predictor and REVEL is consistently + // seen to out-perform other predictors. In our testing we also found that the REVEL-only approach worked best. + + // updated from "Evidence-based calibration of computational tools for missense variant pathogenicity + // classification and ClinGen recommendations for clinical use of PP3/BP4 criteria" + // https://www.biorxiv.org/content/10.1101/2022.03.17.484479v1 + // + var revelScore = pathogenicityData.pathogenicityScore(PathogenicitySource.REVEL); + if (revelScore != null) { + assignRevelBasedPP3BP4Classification(acmgEvidenceBuilder, revelScore); + } else { + // See "Assessing performance of pathogenicity predictors using clinically relevant variant datasets" + // http://dx.doi.org/10.1136/jmedgenet-2020-107003 + assignEnsembleBasedPP3BP4Classification(acmgEvidenceBuilder, pathogenicityData); + } + } + + /* + * Updated classification from "Evidence-based calibration of computational tools for missense variant pathogenicity + * classification and ClinGen recommendations for clinical use of PP3/BP4 criteria" + * https://doi.org/10.1016/j.ajhg.2022.10.013 + * + * This method provided much better + */ + private static void assignRevelBasedPP3BP4Classification(AcmgEvidence.Builder acmgEvidenceBuilder, PathogenicityScore revelScore) { + var revel = revelScore.getRawScore(); + // Taken from table 2 of https://doi.org/10.1016/j.ajhg.2022.10.013 + // P_Strong P_Moderate P_Supporting B_Supporting B_Moderate B_Strong B_Very Strong + // ≥ 0.932 [0.773, 0.932) [0.644, 0.773) (0.183, 0.290] (0.016, 0.183] (0.003, 0.016] ≤ 0.003 + // PATHOGENIC categories + + if (revel >= 0.932f) { + acmgEvidenceBuilder.add(PP3, Evidence.STRONG); + } else if (revel < 0.932f && revel >= 0.773f) { + acmgEvidenceBuilder.add(PP3, Evidence.MODERATE); + } else if (revel < 0.773f && revel >= 0.644f) { + acmgEvidenceBuilder.add(PP3, Evidence.SUPPORTING); + } + // BENIGN categories + // Cap at SUPPORTING as this leads to huge VUS -> LB + else if (revel <= 0.290f) { + acmgEvidenceBuilder.add(BP4, Evidence.SUPPORTING); + } +// else if (revel > 0.183f && revel <= 0.290f) { +// acmgEvidenceBuilder.add(BP4, Evidence.SUPPORTING); +// } else if (revel > 0.016f && revel <= 0.183f) { +// acmgEvidenceBuilder.add(BP4, Evidence.MODERATE); +// } else if (revel > 0.003f && revel <= 0.016f) { +// acmgEvidenceBuilder.add(BP4, Evidence.STRONG); +// } else if (revel <= 0.003f) { +// acmgEvidenceBuilder.add(BP4, Evidence.VERY_STRONG); +// } + + // PM1 & PP3 should only reach a max of STRONG i.e. 4 points + // "Furthermore, it is challenging to separate these shared attributes for tools such as MutPred2 and VEST4 that + // implicitly incorporate some notion of structural and functional importance to each variant position. To address + // this potential overlap or double-counting of PP3/BP4 and PM1, we recommend that laboratories limit the sum of + // the evidence strength of PP3 and PM1 to strong. This would allow PP3 to be invoked as supporting or moderate + // along with PM1 to be invoked as moderate, which would be the same as limiting the sum of PP3 and PM1 to 4 points + // in the Bayes points implementation." + Evidence pm1Ev = acmgEvidenceBuilder.evidenceForCategory(PM1); + Evidence pp3Ev = acmgEvidenceBuilder.evidenceForCategory(PP3); + if (pp3Ev == Evidence.STRONG && pm1Ev != null) { + // defer to PP3 Strong as this should be a lot more sophisticated than the PM1 assignment criteria + logger.debug("Removing PM1_{} as PP3_{} is at threshold of {}", pm1Ev, pp3Ev, Evidence.STRONG); + acmgEvidenceBuilder.remove(PM1); + } + } + + /* + * Ensemble-based approach suggested in + * See "Assessing performance of pathogenicity predictors using clinically relevant variant datasets" + * http://dx.doi.org/10.1136/jmedgenet-2020-107003 + */ + private static void assignEnsembleBasedPP3BP4Classification(AcmgEvidence.Builder acmgEvidenceBuilder, PathogenicityData pathogenicityData) { + int numBenign = 0; + int numPathogenic = 0; + List pathogenicityScores = pathogenicityData.pathogenicityScores(); + for (PathogenicityScore pathogenicityScore : pathogenicityScores) { + if (isPathogenic(pathogenicityScore)) { + numPathogenic++; + } else { + numBenign++; + } + } + if (pathogenicityScores.size() > 1 && numPathogenic > numBenign) { + acmgEvidenceBuilder.add(PP3); + } + if (pathogenicityScores.size() > 1 && numBenign > numPathogenic) { + acmgEvidenceBuilder.add(BP4); + } + } + + private static boolean isPathogenic(PathogenicityScore pathogenicityScore) { + if (pathogenicityScore instanceof SiftScore score) { + return score.getRawScore() < SiftScore.SIFT_THRESHOLD; + } + if (pathogenicityScore instanceof MutationTasterScore score) { + return score.getScore() > MutationTasterScore.MTASTER_THRESHOLD; + } + if (pathogenicityScore instanceof PolyPhenScore score) { + return score.getScore() > PolyPhenScore.POLYPHEN_PROB_DAMAGING_THRESHOLD; + } + if (pathogenicityScore instanceof CaddScore score) { + // 95-99% most deleterious. + return score.getRawScore() >= 13.0f; + } + return pathogenicityScore.getScore() > 0.5f; + } + +} diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java index 8a197862d..710b9fc60 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgPVS1EvidenceAssigner.java @@ -20,7 +20,7 @@ private AcmgPVS1EvidenceAssigner() { /** * Applies PVS1 according to guidelines in Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. - * + *

* PVS1 "null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" */ static void assignPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, Sex probandSex, ModeOfInheritance @@ -49,12 +49,10 @@ static void assignPVS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluati boolean inGeneWithKnownDiseaseAssociations = !knownDiseases.isEmpty(); // TODO should modify the final strength according to ClinGen/GenCC known D2G validity - Table 1 of 10.1002/humu.23626 VariantEffect variantEffect = variantEvaluation.getVariantEffect(); - if (inGeneWithKnownDiseaseAssociations && isLossOfFunctionEffect(variantEffect) - && (modeOfInheritance == ModeOfInheritance.ANY - || compatibleWithRecessive(probandSex, modeOfInheritance) - || compatibleWithDominant(probandSex, modeOfInheritance) && (geneConstraint != null && geneConstraint.isLossOfFunctionIntolerant()) - ) - ) { + if (inGeneWithKnownDiseaseAssociations + && isLossOfFunctionEffect(variantEffect) + && (geneConstraint != null && geneConstraint.isLossOfFunctionIntolerant()) + ){ switch (variantEffect) { case STOP_LOST, STOP_GAINED, FRAMESHIFT_ELONGATION, FRAMESHIFT_TRUNCATION, FRAMESHIFT_VARIANT -> assignNonsenseOrFrameshiftPVS1(acmgEvidenceBuilder, variantEvaluation); @@ -135,11 +133,20 @@ private static boolean predictedToLeadToNmd(VariantEvaluation variantEvaluation) return false; } + // this is a crude method as we don't have the actual transcript coordinates here, so we'll only be able to apply the + // last exon and single exon gene rules private static boolean predictedToLeadToNmd(TranscriptAnnotation transcriptAnnotation) { - // predicted to lead to NMD if in last exon or last 50bp of penultimate exon, or in single exon transcript - boolean notInLastExon = transcriptAnnotation.getRank() < transcriptAnnotation.getRankTotal(); - boolean isSingleExonTranscript = transcriptAnnotation.getRankTotal() == 1; - return transcriptAnnotation.getRankType() == TranscriptAnnotation.RankType.EXON && (notInLastExon || isSingleExonTranscript); + // predicted to lead to NMD if not in last exon or last 50bp of penultimate exon, or is in multi-exon transcript. + // In other words a variant does NOT trigger NMD if it is located: + // - in the last exon + // - in the last 50 bases of the penultimate exon + // - in an exon larger than 400 bases + // - within the first 150 (CDS) bases of the transcription start site + // - in a single-exon gene + boolean notInLastExon = transcriptAnnotation.getRank() < transcriptAnnotation.getRankTotal(); // will be false for single exon genes where rank == rankTotal + VariantEffect variantEffect = transcriptAnnotation.getVariantEffect(); + boolean isExonicOrCanonicalSpliceSite = (transcriptAnnotation.getRankType() == TranscriptAnnotation.RankType.EXON) || variantEffect == VariantEffect.SPLICE_ACCEPTOR_VARIANT || variantEffect == VariantEffect.SPLICE_DONOR_VARIANT; + return isExonicOrCanonicalSpliceSite && notInLastExon; } private static boolean compatibleWithRecessive(Sex probandSex, ModeOfInheritance modeOfInheritance) { diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java index 26bd619d5..9dd1a7d09 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgSpliceEvidenceAssigner.java @@ -32,13 +32,13 @@ private AcmgSpliceEvidenceAssigner() { */ static void assignSpliceEvidence(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ModeOfInheritance modeOfInheritance, List knownDiseases, ClinVarDao clinVarDao) { VariantEffect variantEffect = variantEvaluation.getVariantEffect(); + PathogenicityData pathogenicityData = variantEvaluation.getPathogenicityData(); if (isSpliceDonorAcceptorSpliceVariant(variantEffect)) { // PVS1 decision tree - this should have been independently added by the PVS1EvidenceAssigner class // add PS1 modifier if PVS1 was assigned assignDonorAcceptorPS1(acmgEvidenceBuilder, variantEvaluation, clinVarDao); } else if (isNonDonorAcceptorSpliceRegionVariant(variantEffect)) { // PP3+PS1 or BP4+BP7 - PathogenicityData pathogenicityData = variantEvaluation.getPathogenicityData(); // The database only contains SpliceAI scores > 0.1. This means that any SNP with no score in the database can be considered as // not impacting splicing. PathogenicityScore spliceAiScore = pathogenicityData.pathogenicityScore(PathogenicitySource.SPLICE_AI); @@ -52,6 +52,10 @@ static void assignSpliceEvidence(AcmgEvidence.Builder acmgEvidenceBuilder, Varia } } } + // Note - this is independent of the Splicing guidelines BP7 criteria which is for + // BP7 "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" + ClinVarData clinVarData = pathogenicityData.clinVarData(); + assignSynonymousBP7(acmgEvidenceBuilder, variantEvaluation, pathogenicityData, clinVarData); } private static boolean assignSpliceAiBasedPP3Classification(AcmgEvidence.Builder acmgEvidenceBuilder, float spliceAiScore) { @@ -72,7 +76,7 @@ private static boolean assignSpliceAiBasedPP3Classification(AcmgEvidence.Builder private static void assignNonDonorAcceptorPS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ClinVarDao clinVarDao) { var localClinVarData = getClinVarDataSurroundingVariant(variantEvaluation, clinVarDao); - Set ps1Evidence = EnumSet.noneOf(AcmgCriterion.Evidence.class); + Set ps1Evidence = EnumSet.noneOf(Evidence.class); for (var entry : localClinVarData.entrySet()) { GenomicVariant clinVarVariant = entry.getKey(); ClinVarData clinVarData = entry.getValue(); @@ -121,7 +125,23 @@ private static void assignSilentIntronicBP7(AcmgEvidence.Builder acmgEvidenceBui } } + // BP7 "A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved" + private static void assignSynonymousBP7(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, PathogenicityData pathogenicityData, ClinVarData clinVarData) { + boolean isReportedPorLP = clinVarData.starRating() >= 1 && isPathOrLikelyPath(clinVarData.getPrimaryInterpretation()); + if (variantEvaluation.getVariantEffect() == SYNONYMOUS_VARIANT && !isReportedPorLP) { + PathogenicityScore spliceAiScore = pathogenicityData.pathogenicityScore(PathogenicitySource.SPLICE_AI); + if (spliceAiScore == null || spliceAiScore.getScore() < 0.1) { + acmgEvidenceBuilder.add(BP7); + } + } + } + private static void assignDonorAcceptorPS1(AcmgEvidence.Builder acmgEvidenceBuilder, VariantEvaluation variantEvaluation, ClinVarDao clinVarDao) { + Evidence pvs1Evidence = acmgEvidenceBuilder.evidenceForCategory(PVS1); + if (pvs1Evidence == null) { + return; + } + // find other clinvar variants in same splice region... var localClinVarData = getClinVarDataSurroundingVariant(variantEvaluation, clinVarDao); for (var entry : localClinVarData.entrySet()) { ClinVarData clinVarData = entry.getValue(); @@ -129,17 +149,15 @@ private static void assignDonorAcceptorPS1(AcmgEvidence.Builder acmgEvidenceBuil // Table 2. PS1 code weights for variants with same predicted splicing event as known (likely) pathogenic variant VariantEffect clinVarVariantEffect = clinVarData.getVariantEffect(); if (isSpliceVariant(clinVarVariantEffect) && isPathOrLikelyPath(primaryInterpretation)) { - Set ps1Evidence = EnumSet.noneOf(AcmgCriterion.Evidence.class); - if (acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.VERY_STRONG)) { + Set ps1Evidence = EnumSet.noneOf(Evidence.class); + if (pvs1Evidence == Evidence.VERY_STRONG) { // same position in comparison to VUA if (isSpliceDonorAcceptorSpliceVariant(clinVarVariantEffect) && isPath(primaryInterpretation) || isNonDonorAcceptorSpliceRegionVariant(clinVarVariantEffect) && isLikelyPath(primaryInterpretation)) { ps1Evidence.add(Evidence.SUPPORTING); } } - else if (acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.STRONG) - || acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.MODERATE) - || acmgEvidenceBuilder.containsWithEvidence(PVS1, Evidence.SUPPORTING)) { + else if (pvs1Evidence == Evidence.STRONG || pvs1Evidence == Evidence.MODERATE || pvs1Evidence == Evidence.SUPPORTING) { // same splice region as VUA if (isSpliceDonorAcceptorSpliceVariant(clinVarVariantEffect) && isPath(primaryInterpretation)) { ps1Evidence.add(Evidence.STRONG); @@ -164,11 +182,11 @@ private static Map getClinVarDataSurroundingVariant } private static boolean isPath(ClinVarData.ClinSig clinSig) { - return clinSig == ClinVarData.ClinSig.PATHOGENIC; + return clinSig == ClinVarData.ClinSig.PATHOGENIC || clinSig == ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC; } private static boolean isLikelyPath(ClinVarData.ClinSig clinSig) { - return clinSig == ClinVarData.ClinSig.LIKELY_PATHOGENIC || clinSig == ClinVarData.ClinSig.PATHOGENIC_OR_LIKELY_PATHOGENIC; + return clinSig == ClinVarData.ClinSig.LIKELY_PATHOGENIC; } private static boolean isPathOrLikelyPath(ClinVarData.ClinSig clinSig) { @@ -194,18 +212,17 @@ private static boolean isSpliceDonorAcceptorSpliceVariant(VariantEffect variantE } private static void addPs1Evidence(AcmgEvidence.Builder acmgEvidenceBuilder, Set ps1Evidence) { - for (Evidence evidence : ps1Evidence) { - switch (evidence) { - case STRONG: - acmgEvidenceBuilder.add(PS1); - break; - case MODERATE: - acmgEvidenceBuilder.add(PS1, Evidence.MODERATE); - break; - case SUPPORTING: - acmgEvidenceBuilder.add(PS1, Evidence.SUPPORTING); - break; - } + Evidence maxPs1Strength = null; + if (ps1Evidence.contains(Evidence.STRONG)) { + maxPs1Strength = Evidence.STRONG; + } else if (ps1Evidence.contains(Evidence.MODERATE)) { + maxPs1Strength = Evidence.MODERATE; + } else if (ps1Evidence.contains(Evidence.SUPPORTING)) { + maxPs1Strength = Evidence.SUPPORTING; + } + + if (maxPs1Strength != null) { + acmgEvidenceBuilder.add(PS1, maxPs1Strength); } } diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java index 05bec17c1..39695073f 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/AlleleProtoAdaptor.java @@ -284,7 +284,7 @@ private static Set toClinSigSet(List proto return converted; } - private static ClinVarData.ClinSig toClinSig(ClinVar.ClinSig protoClinSig) { + public static ClinVarData.ClinSig toClinSig(ClinVar.ClinSig protoClinSig) { return switch (protoClinSig) { case BENIGN -> ClinVarData.ClinSig.BENIGN; case BENIGN_OR_LIKELY_BENIGN -> ClinVarData.ClinSig.BENIGN_OR_LIKELY_BENIGN; @@ -308,7 +308,7 @@ private static ClinVarData.ClinSig toClinSig(ClinVar.ClinSig protoClinSig) { }; } - private static ClinVarData.ReviewStatus toReviewStatus(ClinVar.ReviewStatus protoReviewStatus) { + public static ClinVarData.ReviewStatus toReviewStatus(ClinVar.ReviewStatus protoReviewStatus) { return switch (protoReviewStatus) { case NO_ASSERTION_PROVIDED -> ClinVarData.ReviewStatus.NO_ASSERTION_PROVIDED; case NO_ASSERTION_CRITERIA_PROVIDED -> ClinVarData.ReviewStatus.NO_ASSERTION_CRITERIA_PROVIDED; @@ -322,7 +322,7 @@ private static ClinVarData.ReviewStatus toReviewStatus(ClinVar.ReviewStatus prot }; } - private static VariantEffect toVariantEffect(AlleleProto.VariantEffect clinVarVariantEffect) { + public static VariantEffect toVariantEffect(AlleleProto.VariantEffect clinVarVariantEffect) { return switch (clinVarVariantEffect) { case SEQUENCE_VARIANT -> VariantEffect.SEQUENCE_VARIANT; case CHROMOSOME_NUMBER_VARIATION -> VariantEffect.CHROMOSOME_NUMBER_VARIATION; diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java index 5fae61294..9e7178649 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java @@ -27,8 +27,8 @@ import org.junit.jupiter.params.ParameterizedTest; import org.junit.jupiter.params.provider.CsvSource; import org.monarchinitiative.exomiser.core.genome.TestFactory; -import org.monarchinitiative.exomiser.core.genome.TestGenomeDataService; import org.monarchinitiative.exomiser.core.genome.TestVariantDataService; +import org.monarchinitiative.exomiser.core.genome.VariantDataService; import org.monarchinitiative.exomiser.core.model.*; import org.monarchinitiative.exomiser.core.model.Pedigree.Individual.Status; import org.monarchinitiative.exomiser.core.model.frequency.Frequency; @@ -42,7 +42,9 @@ import org.monarchinitiative.exomiser.core.prioritisers.model.Disease; import org.monarchinitiative.exomiser.core.prioritisers.model.InheritanceMode; +import java.util.LinkedHashMap; import java.util.List; +import java.util.Map; import static org.hamcrest.MatcherAssert.assertThat; import static org.hamcrest.Matchers.equalTo; @@ -52,6 +54,7 @@ import static org.monarchinitiative.exomiser.core.model.Pedigree.Individual.Sex.FEMALE; import static org.monarchinitiative.exomiser.core.model.Pedigree.Individual.Sex.MALE; import static org.monarchinitiative.exomiser.core.model.Pedigree.justProband; +import static org.monarchinitiative.exomiser.core.model.pathogenicity.ClinVarData.ClinSig.*; class Acmg2015EvidenceAssignerTest { @@ -60,31 +63,61 @@ private Acmg2015EvidenceAssigner acmgEvidenceAssigner(String probandId, Pedigree return new Acmg2015EvidenceAssigner(probandId, pedigree, TestVariantDataService.stub()); } + private Acmg2015EvidenceAssigner acmgEvidenceAssigner(String probandId, Pedigree pedigree, Map expectedClinVarData) { + return new Acmg2015EvidenceAssigner(probandId, pedigree, TestVariantDataService.builder().expectedClinVarData(expectedClinVarData).build()); + } + @Test void throwsExceptionWithMismatchedIds() { assertThrows(IllegalArgumentException.class, () -> acmgEvidenceAssigner("Zaphod", justProband("Ford", MALE))); } - - @Test - void testAssignsPVS1() { + + @ParameterizedTest + @CsvSource({ + // nonsense, middle-exon NMD predicted + "STOP_LOST, 2, VERY_STRONG", + "STOP_GAINED, 2, VERY_STRONG", + "FRAMESHIFT_ELONGATION, 2, VERY_STRONG", + "FRAMESHIFT_TRUNCATION, 2, VERY_STRONG", + "FRAMESHIFT_VARIANT, 2, VERY_STRONG", + // nonsense, last exon - NMD escape + "STOP_LOST, 5, STRONG", + "STOP_GAINED, 5, STRONG", + "FRAMESHIFT_ELONGATION, 5, STRONG", + "FRAMESHIFT_TRUNCATION, 5, STRONG", + "FRAMESHIFT_VARIANT, 5, STRONG", + // splice donor/acceptor site, middle-exon NMD predicted + "SPLICE_DONOR_VARIANT, 2, VERY_STRONG", + "SPLICE_ACCEPTOR_VARIANT, 2, VERY_STRONG", + // splice donor/acceptor site, last exon - NMD escape + "SPLICE_DONOR_VARIANT, 5, STRONG", + "SPLICE_ACCEPTOR_VARIANT, 5, STRONG", + // transcript ablation / exon loss + "TRANSCRIPT_ABLATION, 2, VERY_STRONG", // sufficient as a STAND_ALONE in the case of HI genes and no conflicting evidence + "EXON_LOSS_VARIANT, 2, VERY_STRONG", // NMD + "EXON_LOSS_VARIANT, 5, STRONG", // NMD escape + // start lost + "START_LOST, 1, MODERATE", + }) + void testAssignsPVS1(VariantEffect variantEffect, int exonNumber, AcmgCriterion.Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); // https://www.ncbi.nlm.nih.gov/clinvar/variation/484600/ 3* PATHOGENIC variant - reviewed by expert panel // requires variant to be on a transcript predicted to undergo NMD in a LoF-intolerant gene for full PVS1 TranscriptAnnotation transcriptAnnotation = TranscriptAnnotation.builder() - .variantEffect(VariantEffect.START_LOST) + .variantEffect(variantEffect) .rankType(TranscriptAnnotation.RankType.EXON) - .rank(1) + .rank(exonNumber) .rankTotal(5) .build(); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") .geneSymbol("PTEN") .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment - .variantEffect(VariantEffect.START_LOST) + .variantEffect(variantEffect) .annotations(List.of(transcriptAnnotation)) .build(); Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); AcmgEvidence acmgEvidence = instance.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(variantEvaluation), List.of(cowdenSyndrome), List.of()); - assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(AcmgCriterion.PVS1).build())); + assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(AcmgCriterion.PVS1, evidence).build())); } @ParameterizedTest @@ -103,7 +136,7 @@ void testAssignsPVS1() { "MALE, X_RECESSIVE, X_RECESSIVE, true", "FEMALE, X_RECESSIVE, X_RECESSIVE, true", - "UNKNOWN, X_RECESSIVE, X_RECESSIVE, false", + "UNKNOWN, X_RECESSIVE, X_RECESSIVE, true", "MALE, X_DOMINANT, X_DOMINANT, true", "FEMALE, X_DOMINANT, X_DOMINANT, true", @@ -113,7 +146,7 @@ void testAssignsPVS1(Pedigree.Individual.Sex probandSex, InheritanceMode disease Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", probandSex)); // https://www.ncbi.nlm.nih.gov/clinvar/variation/484600/ 3* PATHOGENIC variant - reviewed by expert panel TranscriptAnnotation transcriptAnnotation = TranscriptAnnotation.builder() - .variantEffect(VariantEffect.START_LOST) + .variantEffect(VariantEffect.SPLICE_DONOR_VARIANT) .rankType(TranscriptAnnotation.RankType.EXON) .rank(1) .rankTotal(5) @@ -121,7 +154,7 @@ void testAssignsPVS1(Pedigree.Individual.Sex probandSex, InheritanceMode disease VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") .geneSymbol("PTEN") .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment - .variantEffect(VariantEffect.START_LOST) + .variantEffect(VariantEffect.SPLICE_DONOR_VARIANT) .annotations(List.of(transcriptAnnotation)) .build(); Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(diseaseInheritanceMode).diseaseType(Disease.DiseaseType.DISEASE).build(); @@ -131,6 +164,107 @@ void testAssignsPVS1(Pedigree.Individual.Sex probandSex, InheritanceMode disease assertThat(acmgEvidence, equalTo(expected)); } + @ParameterizedTest + @CsvSource({ + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Thr), PATHOGENIC, 3, PS1, STRONG", + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Thr), PATHOGENIC, 2, PS1, STRONG", + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Thr), PATHOGENIC, 1, PS1, MODERATE", + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Thr), PATHOGENIC, 0, PS1, SUPPORTING", + + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Cys), PATHOGENIC, 3, PM5, MODERATE", + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Cys), PATHOGENIC, 2, PM5, MODERATE", + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Cys), PATHOGENIC, 1, PM5, SUPPORTING", + "MISSENSE_VARIANT, p.(Ala42Thr), p.(Ala42Cys), PATHOGENIC, 0, PM5, SUPPORTING", + }) + void testAssignsPS1orPM5(VariantEffect variantEffect, String hgvsP, String clinVarHgvsP, ClinVarData.ClinSig clinSig, int clinVarStarRating, AcmgCriterion acmgCriterion, AcmgCriterion.Evidence evidence) { + ClinVarData clinVarData = ClinVarData.builder() + .primaryInterpretation(clinSig) + .variantEffect(VariantEffect.MISSENSE_VARIANT) + .reviewStatus(starRatingToReviewStatus(clinVarStarRating)) + .hgvsProtein(clinVarHgvsP) + .build(); + Variant overlapping = TestFactory.variantBuilder(10, 89624227, "A", "C").build(); + + VariantDataService variantDataService = TestVariantDataService.builder().put(overlapping, clinVarData).build(); + + TranscriptAnnotation transcriptAnnotation = TranscriptAnnotation.builder() + .variantEffect(variantEffect) + .hgvsProtein(hgvsP) + .build(); + VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") + .geneSymbol("GENE") + .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment + .variantEffect(variantEffect) + .annotations(List.of(transcriptAnnotation)) + .build(); + + Acmg2015EvidenceAssigner instance = new Acmg2015EvidenceAssigner("proband", justProband("proband", MALE), variantDataService); + + Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); + AcmgEvidence acmgEvidence = instance.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(variantEvaluation), List.of(cowdenSyndrome), List.of()); + assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(acmgCriterion, evidence).build())); + } + + private ClinVarData.ReviewStatus starRatingToReviewStatus(int clinVarStarRating) { + return switch (clinVarStarRating) { + case 4 -> ClinVarData.ReviewStatus.PRACTICE_GUIDELINE; + case 3 -> ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL; + case 2 -> ClinVarData.ReviewStatus.CRITERIA_PROVIDED_MULTIPLE_SUBMITTERS_NO_CONFLICTS; + case 1 -> ClinVarData.ReviewStatus.CRITERIA_PROVIDED_SINGLE_SUBMITTER; + default -> ClinVarData.ReviewStatus.NO_ASSERTION_CRITERIA_PROVIDED; + }; + } + + @ParameterizedTest + @CsvSource({ + // requires 4 or more missense P/LP variants in the local region + "1, 3, 0, 0, 0, PM1, MODERATE", + "3, 3, 0, 0, 0, PM1, MODERATE", + "0, 4, 0, 0, 0, PM1, MODERATE", + "0, 4, 3, 0, 0, PM1, MODERATE", + "4, 0, 3, 0, 0, PM1, MODERATE", + "0, 4, 4, 0, 0, PM1, SUPPORTING", + "4, 0, 4, 0, 0, PM1, SUPPORTING", + "0, 0, 0, 0, 0, BP1, SUPPORTING", // Here BP1 is acting as a null marker, results should be empty + "0, 0, 4, 0, 0, BP1, SUPPORTING", // Here BP1 is acting as a null marker, results should be empty + "0, 0, 4, 1, 0, BP1, SUPPORTING", // Here BP1 is acting as a null marker, results should be empty + "4, 0, 4, 1, 0, BP1, SUPPORTING", // Here BP1 is acting as a null marker, results should be empty + "4, 0, 0, 1, 1, BP1, SUPPORTING", // Here BP1 is acting as a null marker, results should be empty + }) + void assignPM1(int p, int lp, int vus, int lb, int b, AcmgCriterion expectedCriteria, Evidence expectedEvidence) { + VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") + .geneSymbol("GENE") + .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment + .variantEffect(VariantEffect.MISSENSE_VARIANT) + .annotations(List.of(TranscriptAnnotation.builder() + .build())) + .build(); + + TestVariantDataService.Builder variantDataServiceBuilder = TestVariantDataService.builder(); + + int[] categoryCounts = {p, lp, vus, lb, b}; + ClinVarData.ClinSig[] categories = {PATHOGENIC, LIKELY_PATHOGENIC, UNCERTAIN_SIGNIFICANCE, LIKELY_BENIGN, BENIGN}; + int currentPos = variantEvaluation.start(); + for (int i = 0; i < categoryCounts.length; i++) { + for (int j = 0; j < categoryCounts[i]; j++) { + Variant variant = TestFactory.variantBuilder(10, ++currentPos, "A", "C").build(); + ClinVarData clinVarData = ClinVarData.builder() + .primaryInterpretation(categories[i]) + .variantEffect(VariantEffect.MISSENSE_VARIANT) + .build(); + variantDataServiceBuilder.put(variant, clinVarData); + } + } + TestVariantDataService variantDataService = variantDataServiceBuilder.build(); + Acmg2015EvidenceAssigner instance = new Acmg2015EvidenceAssigner("proband", justProband("proband", MALE), variantDataService); + + Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); + AcmgEvidence acmgEvidence = instance.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(variantEvaluation), List.of(cowdenSyndrome), List.of()); + AcmgEvidence expected = expectedCriteria == BP1 ? AcmgEvidence.empty() : AcmgEvidence.builder().add(expectedCriteria, expectedEvidence).build(); + assertThat(acmgEvidence, equalTo(expected)); + } + + @Test void testAssignsPS2() { Individual proband = Individual.builder().id("proband").motherId("mother").fatherId("father").sex(MALE).status(Status.AFFECTED).build(); @@ -267,7 +401,7 @@ void testAssignsPM3() { .geneSymbol("PTEN") // n.b. start loss variant - will trigger PVS1 .variantEffect(VariantEffect.START_LOST) - .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(ClinVarData.ClinSig.PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL).build())) + .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL).build())) .sampleGenotypes(SampleGenotypes.of( SampleData.of("proband", SampleGenotype.parseGenotype("1|0")) )) @@ -294,7 +428,7 @@ void testAssignsBP2_InCisWithPathAR() { .build(); VariantEvaluation pathogenic = TestFactory.variantBuilder(10, 89624227, "A", "G") - .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(ClinVarData.ClinSig.PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL).build())) + .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL).build())) .sampleGenotypes(SampleGenotypes.of( SampleData.of("proband", SampleGenotype.parseGenotype("0|1")) )) @@ -329,7 +463,7 @@ void testAssignsBP2_InTransWithPathAD() { .geneSymbol("PTEN") // n.b. start loss variant - will trigger PVS1 .variantEffect(VariantEffect.START_LOST) - .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(ClinVarData.ClinSig.PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL).build())) + .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.REVIEWED_BY_EXPERT_PANEL).build())) .sampleGenotypes(SampleGenotypes.of( SampleData.of("proband", SampleGenotype.parseGenotype("1|0")) )) @@ -402,11 +536,13 @@ void testAssignsPP3() { } @ParameterizedTest - @CsvSource ({ + @CsvSource({ "MVP, 1.0f, , ", - "REVEL, 1.0f, PP3, STRONG" + "REVEL, 1.0f, PP3, STRONG", + "CADD, 0.0f, , ", + "REVEL, 0.0f, BP4, VERY_STRONG" }) - void testAssignsPP3_singleScoreIsInsufficientUnlessItsRevel(PathogenicitySource pathogenicitySource, float pathogenicityScore, AcmgCriterion acmgCriterion, Evidence evidence) { + void testAssignsPP3BP4_singleScoreIsInsufficientUnlessItsRevel(PathogenicitySource pathogenicitySource, float pathogenicityScore, AcmgCriterion acmgCriterion, Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") .geneSymbol("PTEN") @@ -475,26 +611,7 @@ void testAssignsBP4() { assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(AcmgCriterion.BP4).build())); } - @ParameterizedTest - @CsvSource ({ - "CADD, 0.0f, , ", - "REVEL, 0.0f, BP4, VERY_STRONG" - }) - void testAssignsBP4_singleScoreIsInsufficientIfNotRevel(PathogenicitySource pathogenicitySource, float pathogenicityScore, AcmgCriterion acmgCriterion, Evidence evidence) { - Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); - VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") - .geneSymbol("PTEN") - .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment - .pathogenicityData(PathogenicityData.of(PathogenicityScore.of(pathogenicitySource, pathogenicityScore))) - .variantEffect(VariantEffect.MISSENSE_VARIANT) - .build(); - Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); - AcmgEvidence acmgEvidence = instance.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(variantEvaluation), List.of(cowdenSyndrome), List.of()); - - AcmgEvidence expected = acmgCriterion == null ? AcmgEvidence.empty() : AcmgEvidence.builder().add(acmgCriterion, evidence).build(); - assertThat(acmgEvidence, equalTo(expected)); - } - + @Test void testAssignsBP4_majorityMustBeBenign() { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") @@ -513,7 +630,7 @@ void testAssignsBP4_majorityMustBeBenign() { } @ParameterizedTest - @CsvSource ({ + @CsvSource({ "0.932, PP3, STRONG", "0.773, PP3, MODERATE", "0.644f, PP3, SUPPORTING", @@ -550,7 +667,7 @@ public void testRevelOverridesAllOtherScores(float revelScore, AcmgCriterion acm "0.51, SUPPORTING", "0.7, MODERATE", }) - void testAssignsPP4(float phenotypeScore, Evidence evidence) { + void testAssignsPP4(double phenotypeScore, Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") .geneSymbol("PTEN") @@ -587,7 +704,7 @@ void testAssignsPP5(String reviewStatus, AcmgCriterion.Evidence evidence) { .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // n.b. missense variant - will not trigger PVS1 .variantEffect(VariantEffect.MISSENSE_VARIANT) - .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(ClinVarData.ClinSig.PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.parseReviewStatus(reviewStatus)).build())) + .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(PATHOGENIC).reviewStatus(ClinVarData.ReviewStatus.parseReviewStatus(reviewStatus)).build())) .build(); Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); @@ -604,8 +721,8 @@ void testAssignsPP5(String reviewStatus, AcmgCriterion.Evidence evidence) { value = { "criteria provided, single submitter; SUPPORTING", "criteria provided, multiple submitters, no conflicts; STRONG", - "reviewed by expert panel; STRONG", - "practice guideline; STRONG", + "reviewed by expert panel; VERY_STRONG", + "practice guideline; VERY_STRONG", }) void testAssignsBP6(String reviewStatus, AcmgCriterion.Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", Pedigree.empty()); @@ -617,7 +734,7 @@ void testAssignsBP6(String reviewStatus, AcmgCriterion.Evidence evidence) { .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AFRICAN_INC_AFRICAN_AMERICAN, 1.42f))) // n.b. missense variant - will not trigger PVS1 .variantEffect(VariantEffect.MISSENSE_VARIANT) - .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(ClinVarData.ClinSig.BENIGN).reviewStatus(ClinVarData.ReviewStatus.parseReviewStatus(reviewStatus)).build())) + .pathogenicityData(PathogenicityData.of(ClinVarData.builder().primaryInterpretation(BENIGN).reviewStatus(ClinVarData.ReviewStatus.parseReviewStatus(reviewStatus)).build())) .build(); Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); @@ -629,18 +746,32 @@ void testAssignsBP6(String reviewStatus, AcmgCriterion.Evidence evidence) { } } - @Test - void testAssignsBA1() { + @ParameterizedTest + @CsvSource({ + "ESP_AA, true", + "THOUSAND_GENOMES, true", + "TOPMED, true", + "UK10K, true", + "GNOMAD_E_ASJ, false", + "GNOMAD_E_FIN, false", + "GNOMAD_E_OTH, false", + "GNOMAD_G_AMI, false", + "GNOMAD_G_MID, false", + "GNOMAD_E_AFR, true", + "GNOMAD_G_AMR, true", + "GNOMAD_G_NFE, true", + }) + void testAssignsBA1(FrequencySource frequencySource, boolean expected) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") .geneSymbol("PTEN") - // high allele freq - triggers BA1 assignment - .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 5.0f))) + // high allele freq IN A GNOMAD NON-FOUNDER POP - triggers BA1 assignment + .frequencyData(FrequencyData.of(Frequency.of(frequencySource, 5.0f))) .variantEffect(VariantEffect.MISSENSE_VARIANT) .build(); AcmgEvidence acmgEvidence = instance.assignVariantAcmgEvidence(variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(variantEvaluation), List.of(), List.of()); - assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(AcmgCriterion.BA1).build())); + assertThat(acmgEvidence.hasCriterion(AcmgCriterion.BA1), equalTo(expected)); } @Test @@ -689,4 +820,155 @@ void testAssignsBS4() { assertThat(acmgEvidence, equalTo(AcmgEvidence.builder().add(BS4).build())); } + + @Nested + class SplicingEvidence { + + @ParameterizedTest + @CsvSource(value = { + "SPLICE_ACCEPTOR_VARIANT, VERY_STRONG, '', -", + "SPLICE_ACCEPTOR_VARIANT, VERY_STRONG, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, SUPPORTING", + "SPLICE_ACCEPTOR_VARIANT, VERY_STRONG, SPLICE_REGION_VARIANT|PATHOGENIC, -", + "SPLICE_ACCEPTOR_VARIANT, VERY_STRONG, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, SUPPORTING", + "SPLICE_ACCEPTOR_VARIANT, VERY_STRONG, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, SUPPORTING", + "SPLICE_ACCEPTOR_VARIANT, VERY_STRONG, SPLICE_REGION_VARIANT|UNCERTAIN_SIGNIFICANCE:SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, SUPPORTING", + + "SPLICE_ACCEPTOR_VARIANT, STRONG, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_ACCEPTOR_VARIANT, MODERATE, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_ACCEPTOR_VARIANT, SUPPORTING, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_DONOR_VARIANT, STRONG, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_DONOR_VARIANT, MODERATE, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_DONOR_VARIANT, SUPPORTING, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_ACCEPTOR_VARIANT, STRONG, SPLICE_DONOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_ACCEPTOR_VARIANT, MODERATE, SPLICE_DONOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_ACCEPTOR_VARIANT, SUPPORTING, SPLICE_DONOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_DONOR_VARIANT, STRONG, SPLICE_DONOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_DONOR_VARIANT, MODERATE, SPLICE_DONOR_VARIANT|PATHOGENIC, STRONG", + "SPLICE_DONOR_VARIANT, SUPPORTING, SPLICE_DONOR_VARIANT|PATHOGENIC, STRONG", + + "SPLICE_DONOR_VARIANT, STRONG, SPLICE_REGION_VARIANT|PATHOGENIC, MODERATE", + "SPLICE_DONOR_VARIANT, MODERATE, SPLICE_REGION_VARIANT|PATHOGENIC, MODERATE", + "SPLICE_DONOR_VARIANT, SUPPORTING, SPLICE_REGION_VARIANT|PATHOGENIC, MODERATE", + + "SPLICE_DONOR_VARIANT, STRONG, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, SUPPORTING", + "SPLICE_DONOR_VARIANT, MODERATE, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, SUPPORTING", + "SPLICE_DONOR_VARIANT, SUPPORTING, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, SUPPORTING", + + "SPLICE_DONOR_VARIANT, VERY_STRONG, SPLICE_REGION_VARIANT|UNCERTAIN_SIGNIFICANCE, -", + "SPLICE_DONOR_VARIANT, VERY_STRONG, MISSENSE_VARIANT|PATHOGENIC, -", + "SPLICE_DONOR_VARIANT, STRONG, SPLICE_REGION_VARIANT|UNCERTAIN_SIGNIFICANCE, -", + "SPLICE_DONOR_VARIANT, MODERATE, SPLICE_REGION_VARIANT|UNCERTAIN_SIGNIFICANCE, -", + "SPLICE_DONOR_VARIANT, SUPPORTING, SPLICE_REGION_VARIANT|UNCERTAIN_SIGNIFICANCE, -", + }, nullValues = {"-"}) + void testAssignSpliceAcceptorDonorPS1(VariantEffect variantEffect, Evidence pvs1Evidence, String clinVarVariants, Evidence ps1Evidence) { + // https://www.ncbi.nlm.nih.gov/clinvar/variation/484600/ 3* PATHOGENIC variant - reviewed by expert panel + // requires variant to be on a transcript predicted to undergo NMD in a LoF-intolerant gene for full PVS1 + + VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89693009, "G", "C") + .geneSymbol("PTEN") + .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment + .variantEffect(variantEffect) +// .annotations(List.of(transcriptAnnotation)) + .build(); + Map expectedClinVarData = parseExpectedClinvarData(variantEvaluation, clinVarVariants); + Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); + + VariantDataService testVariantDataService = TestVariantDataService.builder().expectedClinVarData(expectedClinVarData).build(); + AcmgEvidence.Builder acmgEvidenceBuilder = AcmgEvidence.builder() + .add(PVS1, pvs1Evidence); + AcmgSpliceEvidenceAssigner.assignSpliceEvidence(acmgEvidenceBuilder, variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(cowdenSyndrome), testVariantDataService); + + AcmgEvidence.Builder expected = AcmgEvidence.builder().add(PVS1, pvs1Evidence); + if (ps1Evidence != null) { + expected.add(PS1, ps1Evidence); + } + assertThat(acmgEvidenceBuilder.build(), equalTo(expected.build())); + } + + @ParameterizedTest + @CsvSource(value = { + "SPLICE_REGION_VARIANT, 0.0, '', BP4", + "SPLICE_REGION_VARIANT, 0.09, '', BP4", + "SPLICE_REGION_VARIANT, 0.1, '', ", + "SPLICE_REGION_VARIANT, 0.2, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, PP3", + "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|PATHOGENIC, PP3 PS1_Strong", + "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, PP3 PS1_Moderate", + // different variant location + "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|PATHOGENIC, PP3 PS1_Moderate", + "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, PP3 PS1_Supporting", + + }) + void testAssignNonDonorAcceptorSpliceRegionPS1(VariantEffect variantEffect, float spliceAiScore, String clinVarVariants, String acmgEvidence) { + // https://www.ncbi.nlm.nih.gov/clinvar/variation/484600/ 3* PATHOGENIC variant - reviewed by expert panel + // requires variant to be on a transcript predicted to undergo NMD in a LoF-intolerant gene for full PVS1 + + VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89693009, "G", "C") + .geneSymbol("PTEN") + .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment + .pathogenicityData(PathogenicityData.of(PathogenicityScore.of(PathogenicitySource.SPLICE_AI, spliceAiScore))) + .variantEffect(variantEffect) + .build(); + Map expectedClinVarData = parseExpectedClinvarData(variantEvaluation, clinVarVariants); + Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); + + VariantDataService testVariantDataService = TestVariantDataService.builder().expectedClinVarData(expectedClinVarData).build(); + AcmgEvidence.Builder acmgEvidenceBuilder = AcmgEvidence.builder(); + AcmgSpliceEvidenceAssigner.assignSpliceEvidence(acmgEvidenceBuilder, variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(cowdenSyndrome), testVariantDataService); + + AcmgEvidence expected = AcmgEvidence.parseAcmgEvidence(acmgEvidence); + assertThat(acmgEvidenceBuilder.build(), equalTo(expected)); + } + + @ParameterizedTest + @CsvSource(value = { + "INTRON_VARIANT, c.300+7A>C, 0.7, ", + "SYNONYMOUS_VARIANT, c.300A>C, 0.3, ", + "SPLICE_REGION_VARIANT, c.300+7A>C, 0.8, PP3", + "SPLICE_REGION_VARIANT, c.300+7A>C, 0.1, ", + "SPLICE_REGION_VARIANT, c.300+6A>C, 0.0, BP4", + "SPLICE_REGION_VARIANT, c.300+7A>C, 0.0, BP4 BP7", + "SPLICE_REGION_VARIANT, c.400-20A>C, 0.0, BP4", + "SPLICE_REGION_VARIANT, c.400-21A>C, 0.0, BP4 BP7", + "SPLICE_REGION_VARIANT, c.400-22A>C, 0.0, BP4 BP7", + }) + void testSilentAndIntronicBP7(VariantEffect variantEffect, String hgvsc, float spliceAiScore, String acmgEvidence) { + TranscriptAnnotation transcriptAnnotation = TranscriptAnnotation.builder() + .variantEffect(variantEffect) + .hgvsCdna(hgvsc) + .build(); + VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") + .geneSymbol("PTEN") + .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment + .pathogenicityData(PathogenicityData.of(PathogenicityScore.of(PathogenicitySource.SPLICE_AI, spliceAiScore))) + .variantEffect(variantEffect) + .annotations(List.of(transcriptAnnotation)) + .build(); + Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); + AcmgEvidence.Builder acmgEvidenceBuilder = AcmgEvidence.builder(); + AcmgSpliceEvidenceAssigner.assignSpliceEvidence(acmgEvidenceBuilder, variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(cowdenSyndrome), TestVariantDataService.stub()); + + AcmgEvidence expected = AcmgEvidence.parseAcmgEvidence(acmgEvidence); + assertThat(acmgEvidenceBuilder.build(), equalTo(expected)); + } + + private Map parseExpectedClinvarData(VariantEvaluation variantEvaluation, String clinVarVariants) { + // SPLICE_ACCEPTOR_VARIANT|PATHOGENIC:SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC:MISSENSE_VARIANT|UNKNOWN_SIGNIFICANCE + if (clinVarVariants.isEmpty()) { + return Map.of(); + } + Map clinVarData = new LinkedHashMap<>(); + String[] clinVars = clinVarVariants.split(":"); + for (int i = 0; i < clinVars.length; i++) { + String[] clinVarInfo = clinVars[i].split("\\|"); + Variant variant = VariantEvaluation.builder().variant(variantEvaluation.contig(), variantEvaluation.strand(), variantEvaluation.coordinates().extend(+i, -i), "A", "T").build(); + ClinVarData clinVar = ClinVarData.builder() + .variantEffect(VariantEffect.valueOf(clinVarInfo[0])) + .primaryInterpretation(ClinVarData.ClinSig.valueOf(clinVarInfo[1])) + .build(); + clinVarData.put(variant, clinVar); + } + return clinVarData; + } + + } } \ No newline at end of file diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java index 05a47eb8a..7ff582073 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java @@ -95,10 +95,10 @@ void calculatePathAcmgAssignments() { gene.addPriorityResult(omimPriorityResult); AcmgEvidence acmgEvidence = AcmgEvidence.builder() - .add(AcmgCriterion.PVS1) + .add(AcmgCriterion.PVS1, AcmgCriterion.Evidence.MODERATE) .add(AcmgCriterion.PM2, AcmgCriterion.Evidence.SUPPORTING) .add(AcmgCriterion.PP3, AcmgCriterion.Evidence.STRONG) - .add(AcmgCriterion.PP4) + .add(AcmgCriterion.PP4, AcmgCriterion.Evidence.MODERATE) .add(AcmgCriterion.PP5, AcmgCriterion.Evidence.VERY_STRONG) .build(); AcmgAssignment acmgAssignment = AcmgAssignment.of(variantEvaluation, gene.getGeneIdentifier(), ModeOfInheritance.AUTOSOMAL_DOMINANT, cowdenSyndrome, acmgEvidence, AcmgClassification.PATHOGENIC); diff --git a/exomiser-data-genome/pom.xml b/exomiser-data-genome/pom.xml index 8e758ec44..fb5a8a3cd 100644 --- a/exomiser-data-genome/pom.xml +++ b/exomiser-data-genome/pom.xml @@ -31,7 +31,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA @@ -48,6 +48,12 @@ org.apache.commons commons-vfs2 2.9.0 + + + commons-logging + commons-logging + + info.picocli @@ -59,6 +65,11 @@ flyway-core ${flyway.version} + + org.duckdb + duckdb_jdbc + 1.0.0 + diff --git a/exomiser-data-phenotype/pom.xml b/exomiser-data-phenotype/pom.xml index 888a26cd9..8d0eab613 100644 --- a/exomiser-data-phenotype/pom.xml +++ b/exomiser-data-phenotype/pom.xml @@ -31,7 +31,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA diff --git a/exomiser-rest-prioritiser/pom.xml b/exomiser-rest-prioritiser/pom.xml index 200bc2409..e890622ae 100644 --- a/exomiser-rest-prioritiser/pom.xml +++ b/exomiser-rest-prioritiser/pom.xml @@ -27,7 +27,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA exomiser-rest-prioritiser diff --git a/exomiser-spring-boot-autoconfigure/pom.xml b/exomiser-spring-boot-autoconfigure/pom.xml index f36eff528..511a9d667 100644 --- a/exomiser-spring-boot-autoconfigure/pom.xml +++ b/exomiser-spring-boot-autoconfigure/pom.xml @@ -35,7 +35,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA diff --git a/exomiser-spring-boot-starter/pom.xml b/exomiser-spring-boot-starter/pom.xml index 92513d85f..18b31bc51 100644 --- a/exomiser-spring-boot-starter/pom.xml +++ b/exomiser-spring-boot-starter/pom.xml @@ -28,7 +28,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA exomiser-spring-boot-starter diff --git a/exomiser-spring-boot-test/pom.xml b/exomiser-spring-boot-test/pom.xml index 11a6ee2cd..b2bc3be56 100644 --- a/exomiser-spring-boot-test/pom.xml +++ b/exomiser-spring-boot-test/pom.xml @@ -27,7 +27,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA exomiser-spring-boot-test diff --git a/exomiser-web/pom.xml b/exomiser-web/pom.xml index 47e0d64ef..f628241fc 100644 --- a/exomiser-web/pom.xml +++ b/exomiser-web/pom.xml @@ -31,7 +31,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA diff --git a/phenix-repository/pom.xml b/phenix-repository/pom.xml index 8fa671333..a500b5e87 100644 --- a/phenix-repository/pom.xml +++ b/phenix-repository/pom.xml @@ -7,7 +7,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA phenix-repository diff --git a/pom.xml b/pom.xml index 614a3c406..a8eb37c2b 100644 --- a/pom.xml +++ b/pom.xml @@ -24,7 +24,7 @@ org.monarchinitiative.exomiser exomiser - 14.0.0 + 14.1.0-ALPHA pom exomiser @@ -172,7 +172,11 @@ com.zaxxer HikariCP - + + org.duckdb + duckdb_jdbc + 1.0.0 + From 5efea2456ada41f4c37fb9955f1fca9335bc631b Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Mon, 2 Sep 2024 10:35:50 +0100 Subject: [PATCH 11/21] Update JannovarSmallVariantAnnotator to remove MNV annotations from effects as these were overriding more damaging functional effects such as STOP_LOSS, STOP_GAIN, SPLICE_DONOR, SPLICE_ACCEPTOR which prevented potential assignment of PVS1. --- .../genome/JannovarSmallVariantAnnotator.java | 19 ++++++++++++++++--- .../core/model/TranscriptAnnotation.java | 9 +++++++++ 2 files changed, 25 insertions(+), 3 deletions(-) diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/JannovarSmallVariantAnnotator.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/JannovarSmallVariantAnnotator.java index ab36e4b5a..01ae4bc2d 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/JannovarSmallVariantAnnotator.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/genome/JannovarSmallVariantAnnotator.java @@ -37,6 +37,7 @@ import java.util.*; import java.util.stream.Stream; +import static de.charite.compbio.jannovar.annotation.VariantEffect.MNV; import static java.util.stream.Collectors.groupingBy; import static java.util.stream.Collectors.toUnmodifiableList; @@ -173,8 +174,11 @@ private List buildTranscriptAnnotations(List a private TranscriptAnnotation toTranscriptAnnotation(Annotation annotation) { AnnotationLocation annoLoc = annotation.getAnnoLoc(); + // add transcript and other variant effects to TranscriptAnnotation? +// annotation.getTranscript() return TranscriptAnnotation.builder() - .variantEffect(getVariantEffectOrDefault(annotation.getMostPathogenicVarType(), VariantEffect.SEQUENCE_VARIANT)) + .variantEffect(getVariantEffectOrDefault(annotation.getEffects(), VariantEffect.SEQUENCE_VARIANT)) +// .variantEffects(annotation.getEffects()) .accession(TranscriptModelUtil.getTranscriptAccession(annotation.getTranscript())) .geneSymbol(buildGeneSymbol(annotation)) .hgvsGenomic((annotation.getGenomicNTChange() == null) ? "" : annotation.getGenomicNTChangeStr()) @@ -199,8 +203,17 @@ private TranscriptAnnotation.RankType getRankType(RankType annoLocRankType) { return TranscriptAnnotation.RankType.UNDEFINED; } - private VariantEffect getVariantEffectOrDefault(VariantEffect annotatedEffect, VariantEffect defaultEffect) { - return annotatedEffect == null ? defaultEffect : annotatedEffect; + private VariantEffect getVariantEffectOrDefault(Collection annotatedEffects, VariantEffect defaultEffect) { + if (annotatedEffects.isEmpty()) { + return defaultEffect; + } + // remove MNV from annotated effects. Jannovar labels block substitutions as MNVs which will override more damaging + // effects such as STOP_LOSS, STOP_GAIN, SPLICE_DONOR, SPLICE_ACCEPTOR and prevent potential assignment of PVS1. + // This could be solved by changing TranscriptAnnotation to have a Set and methods to interrogate + // the state of this e.g. transcriptAnnotation.isStopLoss(), .isStopGain(). n.b. this will also affect + // ClinVarData and VariantEvaluation which currently only use a single VariantEffect field. + return annotatedEffects.size() == 1 ? annotatedEffects.iterator().next() : + annotatedEffects.stream().filter(effect -> effect != MNV).findFirst().orElse(defaultEffect); } private int getDistFromNearestGene(Annotation annotation) { diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/TranscriptAnnotation.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/TranscriptAnnotation.java index 7ba62d7af..372668572 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/TranscriptAnnotation.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/model/TranscriptAnnotation.java @@ -38,6 +38,9 @@ public enum RankType { private final VariantEffect variantEffect; +// private final Set variantEffects; + + private final String geneSymbol; private final String accession; @@ -75,6 +78,10 @@ public VariantEffect getVariantEffect() { return variantEffect; } +// public Set getVariantEffects() { +// return variantEffects; +// } + public String getGeneSymbol() { return geneSymbol; } @@ -148,6 +155,8 @@ public static class Builder { private VariantEffect variantEffect = VariantEffect.SEQUENCE_VARIANT; +// private Set variantEffects = EnumSet.noneOf(VariantEffect.class); + private String geneSymbol = ""; private String accession = ""; From 3587c7061776f50b868f286853e17e6595a87d40 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 3 Sep 2024 14:36:37 +0100 Subject: [PATCH 12/21] Update maven.yml to use v4 GitHub actions --- .github/workflows/maven.yml | 4 ++-- 1 file changed, 2 insertions(+), 2 deletions(-) diff --git a/.github/workflows/maven.yml b/.github/workflows/maven.yml index 5cc773c4e..0e2d08f81 100644 --- a/.github/workflows/maven.yml +++ b/.github/workflows/maven.yml @@ -20,9 +20,9 @@ jobs: runs-on: ubuntu-latest steps: - - uses: actions/checkout@v3 + - uses: actions/checkout@v4 - name: Set up JDK 17 - uses: actions/setup-java@v3 + uses: actions/setup-java@v4 with: java-version: '17' distribution: 'temurin' From f3fa59e57bd19983d479106562c7112201c9509a Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 12 Nov 2024 17:39:02 +0000 Subject: [PATCH 13/21] Deprecate out of date Acmg2015Classifier and Acgs2020Classifier --- .../exomiser/core/analysis/util/acmg/Acgs2020Classifier.java | 2 ++ .../exomiser/core/analysis/util/acmg/Acmg2015Classifier.java | 2 ++ .../core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java | 4 ++-- 3 files changed, 6 insertions(+), 2 deletions(-) diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acgs2020Classifier.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acgs2020Classifier.java index dbd1f1c8b..c884165bf 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acgs2020Classifier.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acgs2020Classifier.java @@ -29,8 +29,10 @@ * Implementation of the ACGS v4 guidelines, Table 3 from * https://www.acgs.uk.com/media/11631/uk-practice-guidelines-for-variant-classification-v4-01-2020.pdf * + * @deprecated Guidelines now suggest using the {@link Acmg2020PointsBasedClassifier} * @since 13.1.0 */ +@Deprecated(since = "14.1.0", forRemoval = true) public final class Acgs2020Classifier implements AcmgEvidenceClassifier { public AcmgClassification classify(AcmgEvidence acmgEvidence) { diff --git a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015Classifier.java b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015Classifier.java index c521839cd..24c2e7026 100644 --- a/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015Classifier.java +++ b/exomiser-core/src/main/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015Classifier.java @@ -29,8 +29,10 @@ * Implementation of the 2015 ACMG Standards guidelines for interpretation of sequence variants (Richards et al. doi:10.1038/gim.2015.30). * Table 5 'Rules for combining criteria to classify sequence variants' * + * @deprecated Guidelines now suggest using the {@link Acmg2020PointsBasedClassifier} * @since 13.1.0 */ +@Deprecated(since = "14.1.0", forRemoval = true) public final class Acmg2015Classifier implements AcmgEvidenceClassifier { public AcmgClassification classify(AcmgEvidence acmgEvidence) { diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java index 7ff582073..4f96d6041 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java @@ -104,7 +104,7 @@ void calculatePathAcmgAssignments() { AcmgAssignment acmgAssignment = AcmgAssignment.of(variantEvaluation, gene.getGeneIdentifier(), ModeOfInheritance.AUTOSOMAL_DOMINANT, cowdenSyndrome, acmgEvidence, AcmgClassification.PATHOGENIC); AcmgEvidenceAssigner acmgEvidenceAssigner = new Acmg2015EvidenceAssigner("proband", justProband("proband", MALE), TestVariantDataService.stub()); - AcmgAssignmentCalculator instance = new AcmgAssignmentCalculator(acmgEvidenceAssigner, new Acgs2020Classifier()); + AcmgAssignmentCalculator instance = new AcmgAssignmentCalculator(acmgEvidenceAssigner, new Acmg2020PointsBasedClassifier()); List acmgAssignments = instance.calculateAcmgAssignments(ModeOfInheritance.AUTOSOMAL_DOMINANT, gene, List.of(variantEvaluation), compatibleDiseaseMatches); assertThat(acmgAssignments, equalTo(List.of(acmgAssignment))); } @@ -138,7 +138,7 @@ void calculateVusAcmgAssignments() { AcmgAssignment acmgAssignment = AcmgAssignment.of(variantEvaluation, gene.getGeneIdentifier(), ModeOfInheritance.AUTOSOMAL_DOMINANT, cowdenSyndrome, acmgEvidence, AcmgClassification.UNCERTAIN_SIGNIFICANCE); AcmgEvidenceAssigner acmgEvidenceAssigner = new Acmg2015EvidenceAssigner("proband", justProband("proband", MALE), TestVariantDataService.stub()); - AcmgAssignmentCalculator instance = new AcmgAssignmentCalculator(acmgEvidenceAssigner, new Acgs2020Classifier()); + AcmgAssignmentCalculator instance = new AcmgAssignmentCalculator(acmgEvidenceAssigner, new Acmg2020PointsBasedClassifier()); List acmgAssignments = instance.calculateAcmgAssignments(ModeOfInheritance.AUTOSOMAL_DOMINANT, gene, List.of(variantEvaluation), compatibleDiseaseMatches); assertThat(acmgAssignments, equalTo(List.of(acmgAssignment))); } From 6a0ac0aa2b545096f688440c9bcd458edaf62f68 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 12 Nov 2024 17:39:45 +0000 Subject: [PATCH 14/21] Update broken ACMG tests --- .../acmg/Acmg2015EvidenceAssignerTest.java | 43 +++++++++++++++---- .../acmg/AcmgAssignmentCalculatorTest.java | 4 +- 2 files changed, 38 insertions(+), 9 deletions(-) diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java index 9e7178649..5866028fd 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/Acmg2015EvidenceAssignerTest.java @@ -540,7 +540,7 @@ void testAssignsPP3() { "MVP, 1.0f, , ", "REVEL, 1.0f, PP3, STRONG", "CADD, 0.0f, , ", - "REVEL, 0.0f, BP4, VERY_STRONG" + "REVEL, 0.0f, BP4, SUPPORTING" }) void testAssignsPP3BP4_singleScoreIsInsufficientUnlessItsRevel(PathogenicitySource pathogenicitySource, float pathogenicityScore, AcmgCriterion acmgCriterion, Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); @@ -636,9 +636,9 @@ void testAssignsBP4_majorityMustBeBenign() { "0.644f, PP3, SUPPORTING", "0.290f, BP4, SUPPORTING", - "0.183f, BP4, MODERATE", - "0.016f, BP4, STRONG", - "0.003f, BP4, VERY_STRONG", + "0.183f, BP4, SUPPORTING", + "0.016f, BP4, SUPPORTING", + "0.003f, BP4, SUPPORTING", }) public void testRevelOverridesAllOtherScores(float revelScore, AcmgCriterion acmgCriterion, Evidence evidence) { Acmg2015EvidenceAssigner instance = acmgEvidenceAssigner("proband", justProband("proband", MALE)); @@ -887,16 +887,13 @@ void testAssignSpliceAcceptorDonorPS1(VariantEffect variantEffect, Evidence pvs1 @ParameterizedTest @CsvSource(value = { + // same variant location "SPLICE_REGION_VARIANT, 0.0, '', BP4", "SPLICE_REGION_VARIANT, 0.09, '', BP4", "SPLICE_REGION_VARIANT, 0.1, '', ", "SPLICE_REGION_VARIANT, 0.2, SPLICE_ACCEPTOR_VARIANT|PATHOGENIC, PP3", "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|PATHOGENIC, PP3 PS1_Strong", "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, PP3 PS1_Moderate", - // different variant location - "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|PATHOGENIC, PP3 PS1_Moderate", - "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, PP3 PS1_Supporting", - }) void testAssignNonDonorAcceptorSpliceRegionPS1(VariantEffect variantEffect, float spliceAiScore, String clinVarVariants, String acmgEvidence) { // https://www.ncbi.nlm.nih.gov/clinvar/variation/484600/ 3* PATHOGENIC variant - reviewed by expert panel @@ -919,6 +916,36 @@ void testAssignNonDonorAcceptorSpliceRegionPS1(VariantEffect variantEffect, floa assertThat(acmgEvidenceBuilder.build(), equalTo(expected)); } + @ParameterizedTest + @CsvSource(value = { + // different variant location + "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|PATHOGENIC, PP3 PS1_Moderate", + "SPLICE_REGION_VARIANT, 0.2, SPLICE_REGION_VARIANT|LIKELY_PATHOGENIC, PP3 PS1_Supporting", + + }) + void testAssignNonDonorAcceptorSpliceRegionPS1VuaDifferentToExistingClinVarVariant(VariantEffect variantEffect, float spliceAiScore, String clinVarVariants, String acmgEvidence) { + VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89693009, "G", "C") + .geneSymbol("PTEN") + .frequencyData(FrequencyData.of(Frequency.of(FrequencySource.EXAC_AMERICAN, 0.1f))) // prevent PM2 assignment + .pathogenicityData(PathogenicityData.of(PathogenicityScore.of(PathogenicitySource.SPLICE_AI, spliceAiScore))) + .variantEffect(variantEffect) + .build(); + + VariantEvaluation knownSpliceRegionVariant = TestFactory.variantBuilder(10, variantEvaluation.start() + 1, "G", "C") + .geneSymbol("PTEN") + .variantEffect(variantEffect) + .build(); + Map expectedClinVarData = parseExpectedClinvarData(knownSpliceRegionVariant, clinVarVariants); + Disease cowdenSyndrome = Disease.builder().diseaseId("OMIM:158350").diseaseName("COWDEN SYNDROME 1; CWS1").inheritanceMode(InheritanceMode.AUTOSOMAL_DOMINANT).diseaseType(Disease.DiseaseType.DISEASE).build(); + + VariantDataService testVariantDataService = TestVariantDataService.builder().expectedClinVarData(expectedClinVarData).build(); + AcmgEvidence.Builder acmgEvidenceBuilder = AcmgEvidence.builder(); + AcmgSpliceEvidenceAssigner.assignSpliceEvidence(acmgEvidenceBuilder, variantEvaluation, ModeOfInheritance.AUTOSOMAL_DOMINANT, List.of(cowdenSyndrome), testVariantDataService); + + AcmgEvidence expected = AcmgEvidence.parseAcmgEvidence(acmgEvidence); + assertThat(acmgEvidenceBuilder.build(), equalTo(expected)); + } + @ParameterizedTest @CsvSource(value = { "INTRON_VARIANT, c.300+7A>C, 0.7, ", diff --git a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java index 4f96d6041..a6f813e12 100644 --- a/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java +++ b/exomiser-core/src/test/java/org/monarchinitiative/exomiser/core/analysis/util/acmg/AcmgAssignmentCalculatorTest.java @@ -66,6 +66,8 @@ void calculatePathAcmgAssignments() { .rankType(TranscriptAnnotation.RankType.EXON) .rank(1) .rankTotal(9) + .hgvsCdna("c.1A>C") + .hgvsProtein("p.0?") .build(); VariantEvaluation variantEvaluation = TestFactory.variantBuilder(10, 89624227, "A", "G") @@ -97,7 +99,7 @@ void calculatePathAcmgAssignments() { AcmgEvidence acmgEvidence = AcmgEvidence.builder() .add(AcmgCriterion.PVS1, AcmgCriterion.Evidence.MODERATE) .add(AcmgCriterion.PM2, AcmgCriterion.Evidence.SUPPORTING) - .add(AcmgCriterion.PP3, AcmgCriterion.Evidence.STRONG) +// .add(AcmgCriterion.PP3, AcmgCriterion.Evidence.STRONG) // not a missense variant .add(AcmgCriterion.PP4, AcmgCriterion.Evidence.MODERATE) .add(AcmgCriterion.PP5, AcmgCriterion.Evidence.VERY_STRONG) .build(); From c0a31cafb6b73bbe1f1ad2b2dba6e24b433049ca Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 12 Nov 2024 17:40:36 +0000 Subject: [PATCH 15/21] Add clnSigLowPenetrance test to ClinVarAlleleParserTest --- .../model/parsers/ClinVarAlleleParserTest.java | 12 ++++++++++++ 1 file changed, 12 insertions(+) diff --git a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java index b24cccfc3..7c787edf1 100644 --- a/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java +++ b/exomiser-data-genome/src/test/java/org/monarchinitiative/exomiser/data/genome/model/parsers/ClinVarAlleleParserTest.java @@ -266,6 +266,18 @@ void unrecognisedClinSigCombo() { assertParseLineEquals(line, List.of(expected)); } + @Test + void clnSigLowPenetrance() { + String line = "1\t94473807\t7888\tC\tT\t.\t.\tALLELEID=22927;RS=1800553;CLNREVSTAT=criteria_provided,_multiple_submitters,_no_conflicts;CLNSIG=Pathogenic/Likely_pathogenic/Pathogenic,_low_penetrance;"; + Allele expected = new Allele(1, 94473807, "C", "T"); + expected.setRsId("1800553"); + expected.setClinVarData(ClinVarData.builder() + .variationId("7888") + .primaryInterpretation(PATHOGENIC_OR_LIKELY_PATHOGENIC) + .reviewStatus(CRITERIA_PROVIDED_MULTIPLE_SUBMITTERS_NO_CONFLICTS) + .build()); + assertParseLineEquals(line, List.of(expected)); + } // 4 6301479 215392 G C . . ALLELEID=211061;CLNDISDB=MedGen:CN517202|MONDO:MONDO:0009101,MedGen:C4551693,OMIM:222300,Orphanet:3463;CLNDN=not_provided|Wolfram_syndrome_1;CLNHGVS=NC_000004.12:g.6301479G>C;CLNREVSTAT=criteria_provided,_multiple_submitters,_no_conflicts;CLNSIG=Likely_pathogenic/Likely_risk_allele;CLNVC=single_nucleotide_variant;CLNVCSO=SO:0001483;CLNVI=ClinGen:CA322818;GENEINFO=WFS1:7466;MC=SO:0001583|missense_variant;ORIGIN=1;RS=753237278 From e12e7c9364178ccfe263a2e20a248f86727b2641 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 12 Nov 2024 17:46:59 +0000 Subject: [PATCH 16/21] Update default_sources.ini with latest URL for hg19 chrToAccessions --- .../src/test/resources/jannovar/default_sources.ini | 12 ++++++------ .../src/main/resources/default_sources.ini | 2 +- .../src/test/resources/default_sources.ini | 2 +- 3 files changed, 8 insertions(+), 8 deletions(-) diff --git a/exomiser-core/src/test/resources/jannovar/default_sources.ini b/exomiser-core/src/test/resources/jannovar/default_sources.ini index ad75402a9..efe2cc684 100644 --- a/exomiser-core/src/test/resources/jannovar/default_sources.ini +++ b/exomiser-core/src/test/resources/jannovar/default_sources.ini @@ -106,7 +106,7 @@ rna=ftp://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/BUILD.36.3/RNA/rna.fa.g type=ucsc alias=MT,M,chrM chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions knownCanonical=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownCanonical.txt.gz knownGene=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownGene.txt.gz @@ -119,7 +119,7 @@ knownToLocusLink=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownTo type = ensembl alias = MT,M,chrM chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions gtf = https://ftp.ensembl.org/pub/grch37/current/gtf/homo_sapiens/Homo_sapiens.GRCh37.87.gtf.gz cdna = https://ftp.ensembl.org/pub/grch37/current/fasta/homo_sapiens/cdna/Homo_sapiens.GRCh37.cdna.all.fa.gz @@ -133,7 +133,7 @@ type = refseq alias = MT,M,chrM allowNonCodingNm = true chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions gff = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/GFF/ref_GRCh37.p13_top_level.gff3.gz rna = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/RNA/rna.fa.gz @@ -146,7 +146,7 @@ alias = MT,M,chrM onlyCurated = true allowNonCodingNm = true chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions gff = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/GFF/ref_GRCh37.p13_top_level.gff3.gz rna = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/RNA/rna.fa.gz @@ -158,7 +158,7 @@ type = refseq alias = MT,M,chrM allowNonCodingNm = true chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions gff = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/GRCh37.p13_interim_annotation/interim_GRCh37.p13_top_level_2017-01-13.gff3.gz rna = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/GRCh37.p13_interim_annotation/interim_GRCh37.p13_rna.fa.gz @@ -171,7 +171,7 @@ alias = MT,M,chrM onlyCurated = true allowNonCodingNm = true chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions gff = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/GRCh37.p13_interim_annotation/interim_GRCh37.p13_top_level_2017-01-13.gff3.gz rna = https://ftp.ncbi.nlm.nih.gov/genomes/H_sapiens/GRCh37.p13_interim_annotation/interim_GRCh37.p13_rna.fa.gz diff --git a/exomiser-data-genome/src/main/resources/default_sources.ini b/exomiser-data-genome/src/main/resources/default_sources.ini index 4588af999..3d4310442 100644 --- a/exomiser-data-genome/src/main/resources/default_sources.ini +++ b/exomiser-data-genome/src/main/resources/default_sources.ini @@ -54,7 +54,7 @@ type=ucsc alias=MT,M,chrM chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/Homo_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions knownCanonical=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownCanonical.txt.gz knownGene=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownGene.txt.gz diff --git a/exomiser-data-genome/src/test/resources/default_sources.ini b/exomiser-data-genome/src/test/resources/default_sources.ini index 7561361a9..a1e6e2fd4 100644 --- a/exomiser-data-genome/src/test/resources/default_sources.ini +++ b/exomiser-data-genome/src/test/resources/default_sources.ini @@ -54,7 +54,7 @@ type=ucsc alias=MT,M,chrM chromInfo = http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/chromInfo.txt.gz -chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/Homo_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 +chrToAccessions = https://ftp.ncbi.nlm.nih.gov/genomes/archive/old_refseq/H_sapiens/ARCHIVE/ANNOTATION_RELEASE.105/Assembled_chromosomes/chr_accessions_GRCh37.p13 chrToAccessions.format = chr_accessions knownCanonical=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownCanonical.txt.gz knownGene=http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/knownGene.txt.gz From a6dce4f464dcb433fdd3530caeb2cdcbca8de4b8 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 12 Nov 2024 17:48:23 +0000 Subject: [PATCH 17/21] Update .circleci/config.yml to use version 2.1 --- .circleci/config.yml | 6 ++++-- 1 file changed, 4 insertions(+), 2 deletions(-) diff --git a/.circleci/config.yml b/.circleci/config.yml index 86976a57a..90b35e73a 100644 --- a/.circleci/config.yml +++ b/.circleci/config.yml @@ -1,4 +1,4 @@ -version: 2 +version: 2.1 jobs: build: working_directory: ~/exomiser @@ -11,7 +11,9 @@ jobs: - image: cimg/openjdk:17.0.7 steps: - checkout - - run: chmod +x mvnw + - run: + name: make executable + command: chmod +x mvnw - restore_cache: key: exomiser-{{ arch }}-{{ checksum "pom.xml" }} - run: ./mvnw clean install -Dmaven.javadoc.skip=true -B -V From a1720b214fce20665e65865ba1fe67d2f4dcf5df Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 12 Nov 2024 17:50:45 +0000 Subject: [PATCH 18/21] Add rocksdb test dependency to exomiser-core and exomiser-data-genome pom.xml --- exomiser-core/pom.xml | 6 ++++++ exomiser-data-genome/pom.xml | 6 ++++++ 2 files changed, 12 insertions(+) diff --git a/exomiser-core/pom.xml b/exomiser-core/pom.xml index 34a8844ca..a6fa88fc8 100644 --- a/exomiser-core/pom.xml +++ b/exomiser-core/pom.xml @@ -139,6 +139,12 @@ jakarta.annotation jakarta.annotation-api + + org.rocksdb + rocksdbjni + 7.6.0 + test + diff --git a/exomiser-data-genome/pom.xml b/exomiser-data-genome/pom.xml index fb5a8a3cd..a5915dffd 100644 --- a/exomiser-data-genome/pom.xml +++ b/exomiser-data-genome/pom.xml @@ -70,6 +70,12 @@ duckdb_jdbc 1.0.0 + + org.rocksdb + rocksdbjni + 7.6.0 + test + From 77f93bd8c577718b115b4fd3c386df106bd097e6 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Wed, 13 Nov 2024 10:40:09 +0000 Subject: [PATCH 19/21] Update pom.xml version to 14.1.0 --- exomiser-cli/pom.xml | 2 +- exomiser-core/pom.xml | 2 +- exomiser-data-genome/pom.xml | 2 +- exomiser-data-phenotype/pom.xml | 2 +- exomiser-rest-prioritiser/pom.xml | 2 +- exomiser-spring-boot-autoconfigure/pom.xml | 2 +- exomiser-spring-boot-starter/pom.xml | 2 +- exomiser-spring-boot-test/pom.xml | 2 +- exomiser-web/pom.xml | 2 +- phenix-repository/pom.xml | 2 +- pom.xml | 2 +- 11 files changed, 11 insertions(+), 11 deletions(-) diff --git a/exomiser-cli/pom.xml b/exomiser-cli/pom.xml index df24df4b5..32e17de19 100644 --- a/exomiser-cli/pom.xml +++ b/exomiser-cli/pom.xml @@ -32,7 +32,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 diff --git a/exomiser-core/pom.xml b/exomiser-core/pom.xml index a6fa88fc8..b4b7f0d79 100644 --- a/exomiser-core/pom.xml +++ b/exomiser-core/pom.xml @@ -30,7 +30,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 diff --git a/exomiser-data-genome/pom.xml b/exomiser-data-genome/pom.xml index a5915dffd..12791d933 100644 --- a/exomiser-data-genome/pom.xml +++ b/exomiser-data-genome/pom.xml @@ -31,7 +31,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 diff --git a/exomiser-data-phenotype/pom.xml b/exomiser-data-phenotype/pom.xml index 8d0eab613..52bced0df 100644 --- a/exomiser-data-phenotype/pom.xml +++ b/exomiser-data-phenotype/pom.xml @@ -31,7 +31,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 diff --git a/exomiser-rest-prioritiser/pom.xml b/exomiser-rest-prioritiser/pom.xml index e890622ae..83a45eb25 100644 --- a/exomiser-rest-prioritiser/pom.xml +++ b/exomiser-rest-prioritiser/pom.xml @@ -27,7 +27,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 exomiser-rest-prioritiser diff --git a/exomiser-spring-boot-autoconfigure/pom.xml b/exomiser-spring-boot-autoconfigure/pom.xml index 511a9d667..782582301 100644 --- a/exomiser-spring-boot-autoconfigure/pom.xml +++ b/exomiser-spring-boot-autoconfigure/pom.xml @@ -35,7 +35,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 diff --git a/exomiser-spring-boot-starter/pom.xml b/exomiser-spring-boot-starter/pom.xml index 18b31bc51..8f55e2184 100644 --- a/exomiser-spring-boot-starter/pom.xml +++ b/exomiser-spring-boot-starter/pom.xml @@ -28,7 +28,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 exomiser-spring-boot-starter diff --git a/exomiser-spring-boot-test/pom.xml b/exomiser-spring-boot-test/pom.xml index b2bc3be56..c153f18fe 100644 --- a/exomiser-spring-boot-test/pom.xml +++ b/exomiser-spring-boot-test/pom.xml @@ -27,7 +27,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 exomiser-spring-boot-test diff --git a/exomiser-web/pom.xml b/exomiser-web/pom.xml index f628241fc..acd3e135a 100644 --- a/exomiser-web/pom.xml +++ b/exomiser-web/pom.xml @@ -31,7 +31,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 diff --git a/phenix-repository/pom.xml b/phenix-repository/pom.xml index a500b5e87..72a9f7d18 100644 --- a/phenix-repository/pom.xml +++ b/phenix-repository/pom.xml @@ -7,7 +7,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 phenix-repository diff --git a/pom.xml b/pom.xml index a8eb37c2b..3d2d0671d 100644 --- a/pom.xml +++ b/pom.xml @@ -24,7 +24,7 @@ org.monarchinitiative.exomiser exomiser - 14.1.0-ALPHA + 14.1.0 pom exomiser From 1dca4e9d601648dd161dfdc4070827412a41afa9 Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Wed, 13 Nov 2024 14:22:14 +0000 Subject: [PATCH 20/21] Update pom.xml genome.data.version and phenotype.data.version properties to 2410 Update cli, prioritiser and web application.properties to use project data.version properties Update exomiser-cli README.md Java version. --- exomiser-cli/README.md | 13 +++++++------ .../src/main/resources/application.properties | 12 ++++++------ .../src/main/resources/application.properties | 2 +- .../src/main/resources/application.properties | 4 ++-- pom.xml | 6 +++--- 5 files changed, 19 insertions(+), 18 deletions(-) diff --git a/exomiser-cli/README.md b/exomiser-cli/README.md index c5f1db419..9c96edeca 100644 --- a/exomiser-cli/README.md +++ b/exomiser-cli/README.md @@ -13,7 +13,8 @@ # The Exomiser - A Tool to Annotate and Prioritize Disease Variants: Command Line Executable -The Exomiser is a tool to perform genome-wide prioritisation of genomic variants including non-coding and regulatory variants using patient phenotypes as a means of differentiating candidate genes. +The Exomiser is a tool to perform genome-wide prioritisation of genomic variants including non-coding and regulatory +variants using patient phenotypes as a means of differentiating candidate genes. To perform an analysis, Exomiser requires the patient's genome/exome in VCF format and their phenotype encoded in HPO terms. The exomiser is also capable of analysing trios/small family genomes, so long as a pedigree in PED format is also @@ -25,7 +26,7 @@ Further information can be found in the [online documentation](https://exomiser. - For exome analysis of a 30,000 variant sample 4GB RAM should suffice. - For genome analysis of a 4,400,000 variant sample 12GB RAM should suffice. - Any 64-bit operating system - - Java 11 or above + - Java 17 or above - At least 50GB free disk space (SSD preferred for best performance) - An internet connection is not required to run the Exomiser, although network access will be required if accessing a networked database (optional). @@ -121,7 +122,7 @@ See the test-analysis-exome.yml and test-analysis-genome.yml files located in th java -Xmx4g -jar exomiser-cli-${project.version}.jar --analysis examples/test-analysis-exome.yml -These files an also be used to run full-genomes, however they will require substantially more RAM to do so. For example +These files can also be used to run full-genomes, however they will require substantially more RAM to do so. For example a 4.4 million variant analysis requires approximately 12GB RAM. However, RAM requirements can be greatly reduced by setting the analysisMode option to PASS_ONLY. This will also aid your ability to evaluate the results. @@ -147,7 +148,7 @@ If you get the following error message: Exception in thread "main" java.lang.UnsupportedClassVersionError: org/monarchinitiative/exomiser/cli/Main : Unsupported major.minor version -You are running an older unsupported version of Java. Exomiser requires java version 11 or higher. This can be checked +You are running an older unsupported version of Java. Exomiser requires Java version 17 or higher. This can be checked by running: java -version @@ -158,8 +159,8 @@ You should see something like this in response: OpenJDK Runtime Environment (build 11.0.11+9-Ubuntu-0ubuntu2.20.04) OpenJDK 64-Bit Server VM (build 11.0.11+9-Ubuntu-0ubuntu2.20.04, mixed mode, sharing) -versions lower than 11 (e.g. 1.5, 1.6, 1.7, 1.8, 9, 10) will not run exomiser, so you will need to install the latest -java version. +versions lower than 17 (e.g. 1.5, 1.6, 1.7, 1.8, 9, 10, 11...) will not run exomiser, so you will need to install the latest +LTS Java version. We recommend using the Eclipse Temurin Java releases which you can find here: https://adoptium.net/ ### Zip file reported as too big or corrupted diff --git a/exomiser-cli/src/main/resources/application.properties b/exomiser-cli/src/main/resources/application.properties index 3387f3a75..78460b1f5 100644 --- a/exomiser-cli/src/main/resources/application.properties +++ b/exomiser-cli/src/main/resources/application.properties @@ -35,7 +35,7 @@ remm.version=0.3.1.post1 cadd.version=1.4 ### hg19 assembly ### -exomiser.hg19.data-version=2402 +exomiser.hg19.data-version=${genome.data.version} # transcript source will default to ensembl. Can define as ucsc/ensembl/refseq #exomiser.hg19.transcript-source=ensembl # location of CADD/REMM Tabix files - you will need these for analysis of non-coding variants. @@ -47,22 +47,22 @@ exomiser.hg19.data-version=2402 # local frequencies are required to be normalised in the same manner as the input VCF and frequency values must be percentages. #exomiser.hg19.local-frequency-path=${exomiser.data-directory}/local/local_frequency_test_hg19.tsv.gz #exomiser.hg19.variant-white-list-path=${exomiser.hg19.data-version}_hg19_clinvar_whitelist.tsv.gz -#exomiser.hg19.clin-var-data-version=2402 +#exomiser.hg19.clin-var-data-version=${genome.data.version} #exomiser.hg19.use-clinvar-white-list=true ### hg38 assembly ### # To enable analysis of samples called against the hg38 assembly copy the hg19 above and just replace the hg19 with hg38 -#exomiser.hg38.data-version=2402 +#exomiser.hg38.data-version=${genome.data.version} #exomiser.hg38.cadd-snv-path=${exomiser.data-directory}/cadd/${cadd.version}/whole_genome_SNVs.tsv.gz #exomiser.hg38.cadd-in-del-path=${exomiser.data-directory}/cadd/${cadd.version}/InDels.tsv.gz #exomiser.hg38.remm-path=${exomiser.data-directory}/remm/ReMM.v${remm.version}.hg38.tsv.gz #exomiser.hg38.local-frequency-path=${exomiser.data-directory}/local/local_frequency_test_hg38.tsv.gz #exomiser.hg38.variant-white-list-path=${exomiser.hg38.data-version}_hg38_clinvar_whitelist.tsv.gz -#exomiser.hg38.clin-var-data-version=2402 +#exomiser.hg38.clin-var-data-version=${genome.data.version} #exomiser.hg38.use-clinvar-white-list=true ### phenotypes ### -exomiser.phenotype.data-version=2402 +exomiser.phenotype.data-version=${phenotype.data.version} #exomiser.phenotype.data-directory=${exomiser.data-directory}/${exomiser.phenotype.data-version}_phenotype # String random walk data file #exomiser.phenotype.random-walk-file-name=rw_string_10.mv @@ -81,4 +81,4 @@ exomiser.phenotype.data-version=2402 ### logging ### # Logging is highly configurable - see https://docs.spring.io/spring-boot/docs/current/reference/html/features.html#features.logging.file-output #logging.file.name=logs/exomiser.log -logging.level.com.zaxxer.hikari=ERROR \ No newline at end of file +logging.level.com.zaxxer.hikari=ERROR ${java.version} \ No newline at end of file diff --git a/exomiser-rest-prioritiser/src/main/resources/application.properties b/exomiser-rest-prioritiser/src/main/resources/application.properties index fbfb8e6cc..ec319ab77 100644 --- a/exomiser-rest-prioritiser/src/main/resources/application.properties +++ b/exomiser-rest-prioritiser/src/main/resources/application.properties @@ -25,7 +25,7 @@ server.servlet.application-display-name=Exomiser Prioritiser Server #Absolute system path where the exomiser data is installed exomiser.data-directory=${project.build.testOutputDirectory} -exomiser.phenotype.data-version=1707 +exomiser.phenotype.data-version=${phenotype.data.version} exomiser.phenotype.random-walk-preload=true #Actuator configuration diff --git a/exomiser-web/src/main/resources/application.properties b/exomiser-web/src/main/resources/application.properties index 167a386d7..717acb6c8 100644 --- a/exomiser-web/src/main/resources/application.properties +++ b/exomiser-web/src/main/resources/application.properties @@ -44,7 +44,7 @@ exomiser.web.max-genes=30 exomiser.web.clinical-instance=false # Configure the Exomiser properties - use the exomiser-cli application.properties as a template exomiser.data-directory=${data.dir} -#exomiser.hg19.data-version=2109 +#exomiser.hg19.data-version=${genome.data.version} #exomiser.hg19.variant-white-list-path=${exomiser.hg19.data-version}_hg19_clinvar_whitelist.tsv.gz -#exomiser.phenotype.data-version=2109 +#exomiser.phenotype.data-version=${phenotype.data.version} exomiser.phenotype.random-walk-preload=true \ No newline at end of file diff --git a/pom.xml b/pom.xml index 3d2d0671d..c4a88dc7b 100644 --- a/pom.xml +++ b/pom.xml @@ -109,9 +109,9 @@ docker.io exomiser - - 2402 - 2402 + + 2410 + 2410 From 55ca70116aa11339b9869e27632ef6ba86658eaf Mon Sep 17 00:00:00 2001 From: Jules Jacobsen Date: Tue, 10 Dec 2024 14:37:39 +0000 Subject: [PATCH 21/21] Update CHANGELOG.md --- exomiser-cli/CHANGELOG.md | 263 ++++++++++++++++++++++++++----------- exomiser-core/CHANGELOG.md | 183 +++++++++++++++++++------- 2 files changed, 315 insertions(+), 131 deletions(-) diff --git a/exomiser-cli/CHANGELOG.md b/exomiser-cli/CHANGELOG.md index 618ae1dc9..b21be4054 100644 --- a/exomiser-cli/CHANGELOG.md +++ b/exomiser-cli/CHANGELOG.md @@ -1,66 +1,104 @@ # The Exomiser Command Line Executable - Changelog +## 14.1.0 2024-11-14 + +Further updates to ACMG assignment categories, including addition of PS1, PM1, PM5, BS1, BS2 categories to ACMG +assignments. + +- New AcmgMissenseInFrameIndelEvidenceAssigner class to assign PS1, PM1, PM5, PP2, BP1, PP3, BP4 to missense and inframe + indels. +- New AcmgSpliceEvidenceAssigner class which applies PS1, PP3, BP4, BP7 to splice region variants according to ClinGen + recommendations for splicing variants published in + [Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations + from the ClinGen SVI Splicing Subgroup](https://doi.org/10.1016/j.ajhg.2023.06.002). +- New AcmgPVS1EvidenceAssigner handles assignment of PVS1 to loss of function variants according + to [Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion](https://doi.org/10.1002/humu.23626) +- Downgraded BP4 to have a maximum of `Supporting` evidence for REVEL scores under 0.290 + ## 14.0.2 2024-09-20 -- Fix for issue #571. This is a bug-fix release to prevent erroneous assignment of `PVS1` to recessive-compatible variants in LOF-tolerant genes. +- Fix for issue [#571](https://github.com/exomiser/Exomiser/issues/571). This is a bug-fix release to prevent erroneous + assignment of `PVS1` to recessive-compatible variants in LOF-tolerant genes. ## 14.0.1 2024-09-03 - -- Fix for Issue #565. This is a patch release to prevent a possible ArrayIndexOutOfBoundsException being thrown when outputting the variants TSV file. There are no other changes. + +- Fix for Issue [#565](https://github.com/exomiser/Exomiser/issues/565). This is a patch release to prevent a possible + ArrayIndexOutOfBoundsException being thrown when outputting the variants TSV file. There are no other changes. ## 14.0.0 2024-02-29 - Minimum Java version is now **Java 17** -- Update database format **REQUIRES DATABASE VERSION 2402** - these are significantly smaller than the previous versions (~50-60% of previous size) +- Update database format **REQUIRES DATABASE VERSION 2402** - these are significantly smaller than the previous + versions (~50-60% of previous size) - Added new GeneBlacklistFilter [#457](https://github.com/exomiser/Exomiser/issues/457) - Add new ClinVar conflicting evidence counts in HTML output [#535](https://github.com/exomiser/Exomiser/issues/535) - Added PS1, PM1, PM5 categories to ACMG assignments - Altered reporting of InheritanceModeFilter to state that the number shown refers to variants rather than genes. - Updated gene constraints to use gnomad v4.0 data. -- TSV genes, TSV variants and VCF outputs will only write to a single file where the possible modes of inheritances are now shown together rather than split across separate files. -- Fix for issue [#531](https://github.com/exomiser/Exomiser/issues/531) where the `priorityScoreFilter` and `regulatoryFeatureFilter` pass/fail counts were not displayed in the HTML. -- Fix for issue [#534](https://github.com/exomiser/Exomiser/issues/534) where variant frequency and/or pathogenicity annotations are missing in certain run configurations. -- Fix for issue [#541](https://github.com/exomiser/Exomiser/issues/541) where logging to /tmp/spring.log causes clashes in shared user environments. -- TSV output column `CLINVAR_ALLELE_ID` has been changed to `CLINVAR_VARIANT_ID` to allow easier reference to ClinVar variants. +- TSV genes, TSV variants and VCF outputs will only write to a single file where the possible modes of inheritances are + now shown together rather than split across separate files. +- Fix for issue [#531](https://github.com/exomiser/Exomiser/issues/531) where the `priorityScoreFilter` and + `regulatoryFeatureFilter` pass/fail counts were not displayed in the HTML. +- Fix for issue [#534](https://github.com/exomiser/Exomiser/issues/534) where variant frequency and/or pathogenicity + annotations are missing in certain run configurations. +- Fix for issue [#541](https://github.com/exomiser/Exomiser/issues/541) where logging to /tmp/spring.log causes clashes + in shared user environments. +- TSV output column `CLINVAR_ALLELE_ID` has been changed to `CLINVAR_VARIANT_ID` to allow easier reference to ClinVar + variants. ## 13.3.0 2023-10-17 -- Updated Jannovar version to 0.41 to fix incorrect MT codon table usage [#521](https://github.com/exomiser/Exomiser/issues/521) -- Downgraded PM2 - PM2_Supporting for variants lacking frequency information [#502](https://github.com/exomiser/Exomiser/issues/502). +- Updated Jannovar version to 0.41 to fix incorrect MT codon table + usage [#521](https://github.com/exomiser/Exomiser/issues/521) +- Downgraded PM2 - PM2_Supporting for variants lacking frequency + information [#502](https://github.com/exomiser/Exomiser/issues/502). - Updated AcmgEvidence to fit a Bayesian points-based system [#514](https://github.com/exomiser/Exomiser/issues/514) -- Removed ASJ, FIN, OTH ExAC and gnomAD populations from presets and examples [#513](https://github.com/exomiser/Exomiser/issues/513). +- Removed ASJ, FIN, OTH ExAC and gnomAD populations from presets and + examples [#513](https://github.com/exomiser/Exomiser/issues/513). - Fix for regression causing `` variants to be incorrectly down-ranked -- Fix for issue [#486](https://github.com/exomiser/Exomiser/issues/486) where VCF output includes whitespace in INFO field. -- Logs will now display elapsed time correctly if an analysis runs over an hour (!). +- Fix for issue [#486](https://github.com/exomiser/Exomiser/issues/486) where VCF output includes whitespace in INFO + field. +- Logs will now display elapsed time correctly if an analysis runs over an hour (!). ## 13.2.1 2023-06-30 -- Fix for bug where all `` structural variants were given a maximal variant score of 1.0 regardless of their position on a transcript. -- Added partial implementation of [SVanna scoring](https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01046-6/tables/1) for coding and splice site symbolic variants. -- Fix for issue #481 where TSV and VCF results files would contain no data when the analysis `inheritanceModes` was empty. +- Fix for bug where all `` structural variants were given a maximal variant score of 1.0 regardless of their + position on a transcript. +- Added partial implementation + of [SVanna scoring](https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01046-6/tables/1) for coding + and splice site symbolic variants. +- Fix for issue #481 where TSV and VCF results files would contain no data when the analysis `inheritanceModes` was + empty. -**IMPORTANT!** *This will be the last major release to run on Java 11. Subsequent major releases (i.e. 14+) will require Java 17.* +**IMPORTANT!** *This will be the last major release to run on Java 11. Subsequent major releases (i.e. 14+) will require +Java 17.* ## 13.2.0 2023-02-28 - - New multi-architecture docker images with and without bash [#471](https://github.com/exomiser/Exomiser/issues/470) - - Deprecated of `output-prefix` CLI option (will be removed in next major version) [#469](https://github.com/exomiser/Exomiser/issues/469) - - Added `output-directory` and `output-filename` CLI options to replace `output-prefix` [#469](https://github.com/exomiser/Exomiser/issues/469) - - Added `output-format` CLI option [#471](https://github.com/exomiser/Exomiser/issues/471) - - Fixed excessive CPU usage and application hang after variant prioritisation with large number of results - - Fixed issue [#478](https://github.com/exomiser/Exomiser/issues/478) where gene.tsv output files are empty when running a phenotype only prioritisation. - - Fixed broken links to OMIM in the phenotypic similarity section of the HTML output [#465](https://github.com/exomiser/Exomiser/issues/465) - - Added gene symbol as HTML id tag in gene panel HTML results [#422](https://github.com/exomiser/Exomiser/pull/422) +- New multi-architecture docker images with and without bash [#471](https://github.com/exomiser/Exomiser/issues/470) +- Deprecated of `output-prefix` CLI option (will be removed in next major + version) [#469](https://github.com/exomiser/Exomiser/issues/469) +- Added `output-directory` and `output-filename` CLI options to replace + `output-prefix` [#469](https://github.com/exomiser/Exomiser/issues/469) +- Added `output-format` CLI option [#471](https://github.com/exomiser/Exomiser/issues/471) +- Fixed excessive CPU usage and application hang after variant prioritisation with large number of results +- Fixed issue [#478](https://github.com/exomiser/Exomiser/issues/478) where gene.tsv output files are empty when running + a phenotype only prioritisation. +- Fixed broken links to OMIM in the phenotypic similarity section of the HTML + output [#465](https://github.com/exomiser/Exomiser/issues/465) +- Added gene symbol as HTML id tag in gene panel HTML results [#422](https://github.com/exomiser/Exomiser/pull/422) ## 13.1.0 2022-07-29 - Added new automated ACMG annotations for top-scoring variants in known disease-causing genes. - Added new combined score p-value - Added new TSV_GENE, TSV_VARIANT and VCF output files containing ranked genes/variants for all the assessed modes of - inheritance. Note that __these new file formats will supersede the existing individual MOI-specific TSV/VCF files which - will be removed in the next major release__. See the [online documentation](https://exomiser.readthedocs.io/en/latest/result_interpretation.html) for details. + inheritance. Note that __these new file formats will supersede the existing individual MOI-specific TSV/VCF files + which + will be removed in the next major release__. See + the [online documentation](https://exomiser.readthedocs.io/en/latest/result_interpretation.html) for details. - New update online documentation! See https://exomiser.readthedocs.io/en/latest/ -- New Docker hub images for CLI and web on https://hub.docker.com/u/exomiser +- New Docker hub images for CLI and web on https://hub.docker.com/u/exomiser - Added checks to ensure user specifies genome assembly if user specifies vcf path outside of phenopacket/analysis - Added `--output-prefix` option to enable output prefix directly on the command line - Updated examples to use the latest recommended settings as per preset derived from 100,000 genomes project @@ -103,16 +141,21 @@ whitelist and 'second generation' pathogenicity scores. status. ## 11.0.0 2018-09-21 + - Removed ```analysisMode: SPARSE``` option - this will default to ```PASS_ONLY``` -- Removed ```phenixPrioritiser: {}``` option - we recommend using ```hiPhivePrioritiser: {runParams: 'human'}``` for human-only model comparisons -- Changed ```outputPassVariantsOnly``` to ```outputContributingVariantsOnly``` in ```outputOptions```. Enabling this will only report the variants marked as ```CONTRIBUTING_VARIANT```, _i.e._ those variants which contribute to the ```EXOMISER_GENE_VARIANT_SCORE``` and ```EXOMISER_GENE_COMBINED_SCORE``` score. This will default to ```false```. +- Removed ```phenixPrioritiser: {}``` option - we recommend using ```hiPhivePrioritiser: {runParams: 'human'}``` for + human-only model comparisons +- Changed ```outputPassVariantsOnly``` to ```outputContributingVariantsOnly``` in ```outputOptions```. Enabling this + will only report the variants marked as ```CONTRIBUTING_VARIANT```, _i.e._ those variants which contribute to the + ```EXOMISER_GENE_VARIANT_SCORE``` and ```EXOMISER_GENE_COMBINED_SCORE``` score. This will default to ```false```. ```yaml outputOptions: outputContributingVariantsOnly: false ``` ## 10.1.0 2018-05-09 -- Added support for filtering multiple intervals in the ```intervalFilter``` + +- Added support for filtering multiple intervals in the ```intervalFilter``` ```yaml # single interval intervalFilter: {interval: 'chr10:123256200-123256300'}, @@ -121,18 +164,24 @@ whitelist and 'second generation' pathogenicity scores. # or using a BED file - NOTE this should be 0-based, Exomiser otherwise uses 1-based coordinates in line with VCF intervalFilter: {bed: /full/path/to/bed_file.bed} ``` -- Added support for ClinVar annotations - available in the 1805 variant data release. These will appear automatically and are reported for information only. +- Added support for ClinVar annotations - available in the 1805 variant data release. These will appear automatically + and are reported for information only. - Added ```JSON``` output format ```yaml outputFormats: [HTML, JSON, TSV_GENE, TSV_VARIANT, VCF] ``` ## 10.0.1 2018-03-20 + - Updated HTSJDK library to fix ```TribbleException``` being thrown when trying to parse bgzipped VCF files ## 10.0.0 2018-03-07 -- Deprecated extended cli options as these were less capable than the analysis file. Options are now ```--analysis``` or ```--analysis-batch``` only. See the ```.yml``` files in the ```examples``` directory for recommended scripts. -- Exomiser can now analyse samples against multiple inheritance modes in one run using the new ```inheritanceModes``` field. This also allows variants to be considered under a model with a maximum frequency (%) cut-off. See example ```.yml``` files for more details. + +- Deprecated extended cli options as these were less capable than the analysis file. Options are now ```--analysis``` or + ```--analysis-batch``` only. See the ```.yml``` files in the ```examples``` directory for recommended scripts. +- Exomiser can now analyse samples against multiple inheritance modes in one run using the new ```inheritanceModes``` + field. This also allows variants to be considered under a model with a maximum frequency (%) cut-off. See example + ```.yml``` files for more details. ```yaml inheritanceModes: { AUTOSOMAL_DOMINANT: 0.1, @@ -144,146 +193,199 @@ whitelist and 'second generation' pathogenicity scores. MITOCHONDRIAL: 0.2 } ``` -- The old ```modeOfInheritance``` option will still work, although it will only run with default frequency cut-offs and may be removed in a later release, so please update your analyses. -- The new ```1802_phenotype``` data release will not work on older exomiser versions as the PPI data is now shipped in a much more efficient storage format. This reduces the startup time to zero and reduces the memory footprint by approx 1 GB. We *highly* recommend you update older releases to the latest version in order to benefit from more recent phenotype data. -- Default variant scores for ```FRAMESHIFT```, ```NONSENSE```, ```SPLICING```, ```STOPLOSS``` and ```STARTLOSS``` have been increased from 0.95 to the maximum score of 1.0 to reflect clinical interpretation of these variant consequences. +- The old ```modeOfInheritance``` option will still work, although it will only run with default frequency cut-offs and + may be removed in a later release, so please update your analyses. +- The new ```1802_phenotype``` data release will not work on older exomiser versions as the PPI data is now shipped in a + much more efficient storage format. This reduces the startup time to zero and reduces the memory footprint by approx 1 + GB. We *highly* recommend you update older releases to the latest version in order to benefit from more recent + phenotype data. +- Default variant scores for ```FRAMESHIFT```, ```NONSENSE```, ```SPLICING```, ```STOPLOSS``` and ```STARTLOSS``` have + been increased from 0.95 to the maximum score of 1.0 to reflect clinical interpretation of these variant consequences. ## 9.0.1 2018-01-15 + - Now able to analyse ```MITOCHONDRIAL``` inheritance mode. ## 9.0.0 2017-12-12 + - Exomiser can now analyse hg19 or hg38 samples - see ```application.properties``` for setup details. -- Analysis file has new ```genomeAssembly:``` field - see example ```.yml``` files. Will default to hg19 if not specified. -- Genomic and phenotypic data are now separated to allow for more frequent and smaller updates - see README.md for details -- Variant alleles are now stored in a new highly-compressed data format enabling much smaller on-disk footprint with minimal loss of read performance. +- Analysis file has new ```genomeAssembly:``` field - see example ```.yml``` files. Will default to hg19 if not + specified. +- Genomic and phenotypic data are now separated to allow for more frequent and smaller updates - see README.md for + details +- Variant alleles are now stored in a new highly-compressed data format enabling much smaller on-disk footprint with + minimal loss of read performance. - New variant frequency data-sets: TOPMed, UK10K, gnomAD - see example ```.yml``` files. - New caching mechanism - see ```application.properties``` for setup details. ## 8.0.0 2017-08-08 + - See https://github.com/exomiser/Exomiser/projects/2 for a complete list of changes. -- ```application.properties``` file has changed to use ```exomiser``` namespace prefix. Will allow property placeholder substitution - e.g. ```exomiser.property=foo``` can be used elsewhere in the file as ```${exomiser.property}```. Will support user-defined property values too. -- Analysis file now requires ```proband``` id to be specified. Bug-fix for multi-sample VCF files where the proband sample is not the first sample in the genotypes section leading to occasional scores of 0 for the exomiser_gene_variant_score in cases where the variants are heterozygous and consistent with autosomal recessive. +- ```application.properties``` file has changed to use ```exomiser``` namespace prefix. Will allow property placeholder + substitution - e.g. ```exomiser.property=foo``` can be used elsewhere in the file as ```${exomiser.property}```. Will + support user-defined property values too. +- Analysis file now requires ```proband``` id to be specified. Bug-fix for multi-sample VCF files where the proband + sample is not the first sample in the genotypes section leading to occasional scores of 0 for the + exomiser_gene_variant_score in cases where the variants are heterozygous and consistent with autosomal recessive. - Analysis file ```scoringMode``` option has now been removed as it was never used. -- Analysis now supports a new ```failedVariantFilter: {}``` to remove variants without a ```PASS``` or ```.``` in the FILTER field. +- Analysis now supports a new ```failedVariantFilter: {}``` to remove variants without a ```PASS``` or ```.``` in the + FILTER field. - Can now filter variants by LOCAL frequency source. - It is now possible to use UCSC, ENSEMBL or REFSEQ transcript identifiers. -- REMM data is no longer bundled with the distribution. If you want to use this for non-coding variant pathogenicity scoring you'll need to manually download and install it. +- REMM data is no longer bundled with the distribution. If you want to use this for non-coding variant pathogenicity + scoring you'll need to manually download and install it. - Memory requirements are now reduced. - Fixed AR comp-het scoring bug. - Now partly normalises incoming variant data enabling better performance for multi-allelic sites. - Variants contributing to the exomiser score are now flagged in output files. - VCF output now has valid headers for info fields and more informative information. - VCF output no longer contain invalid values in FILTER field for failed variants. -- VCF lines containing multiple alleles now contain the field ```ExContribAltAllele``` with an zero-based integer indicating the ALT allele contributing to the score. +- VCF lines containing multiple alleles now contain the field ```ExContribAltAllele``` with an zero-based integer + indicating the ALT allele contributing to the score. - HTML output now shows individual variant scores and flags contributing variants along with displaying them first. - HTML output tweaked to display data more clearly in the genes section. +## 7.2.3 2016-11-02 + +- Partial bug-fix for multi-sample VCF files where the proband sample is not the first sample in the genotypes section + leading to occasional scores of 0 for the exomiser_gene_variant_score in cases where the variants are heterozygous and + consistent with autosomal recessive. -## 7.2.3 2016-11-02 -- Partial bug-fix for multi-sample VCF files where the proband sample is not the first sample in the genotypes section leading to occasional scores of 0 for the exomiser_gene_variant_score in cases where the variants are heterozygous and consistent with autosomal recessive. +*IMPORTANT!* As a workaround for this issue ensure the proband sample is the first sample in the VCF file. This will be +properly fixed in the next major release. -*IMPORTANT!* As a workaround for this issue ensure the proband sample is the first sample in the VCF file. This will be properly fixed in the next major release. +## 7.2.2 2016-07-01 -## 7.2.2 2016-07-01 -- Fix for issue when using OmimPrioritiser with UNDEFINED inheritance mode which led to gene phenotype scores being halved. -- Fix for VCF output multiple allele line duplications. VCF output will now have alternate alleles written out on the same line if they were originally like that in the input VCF. The variant scores will be concatenated to correspond with the alleles. VCFs containing alleles split onto seperate lines in the input file will continue to have them like this in the output file. +- Fix for issue when using OmimPrioritiser with UNDEFINED inheritance mode which led to gene phenotype scores being + halved. +- Fix for VCF output multiple allele line duplications. VCF output will now have alternate alleles written out on the + same line if they were originally like that in the input VCF. The variant scores will be concatenated to correspond + with the alleles. VCFs containing alleles split onto seperate lines in the input file will continue to have them like + this in the output file. ## 7.2.1 2016-01-05 -- Fix for incorrect inheritance mode calculations where the variant chromosome number is prefixed with 'chr' in VCF file. + +- Fix for incorrect inheritance mode calculations where the variant chromosome number is prefixed with 'chr' in VCF + file. ## 7.2.0 2015-11-25 -- Performance in identification of causal regulatory variants as the top candidate of simulated whole genomes now improved to over 80%. + +- Performance in identification of causal regulatory variants as the top candidate of simulated whole genomes now + improved to over 80%. - Enhancer variants are assigned to TADs - Variant gene assignment improvements and bug-fixes. ## 7.1.0 2015-10-21 + - Variants in FANTOM5 enhancer and ENSEMBLE regulatory regions are now all marked REGULATORY_REGION_VARIANT even without - the regulatoryFeatureFilter being run. + the regulatoryFeatureFilter being run. - Massive performance increase when running regulatoryFeatureFilter. - Running Exomiser in exome analysis mode now requires REGULATORY_FEATURE to be included in the variantEffectFilter. -See test-analysis-exome.yml + See test-analysis-exome.yml - Added missing regulatoryFeatureFilter step from the analysis steps in test-analysis-genome.yml ## 7.0.0 2015-10-01 + Now requires Java 8 or higher to run. + - The Exomiser is now somewhat inaccurately named as it can now analyse whole-genome samples. - Exomiser is now much more customisable with the new analysis YAML configuration files. See test-analysis-exome.yml and - test-analysis-genome.yml for examples + test-analysis-genome.yml for examples - Added new --analysis and --analysis-batch commands to be used with the new analysis format. - New PASS_ONLY analysis mode. Exomiser will only keep variants which passed filters. This allows for dramatically -reduced memory requirements which is especially handy for genome-sized analyses. -- Exomiser now ships with a new pathogenicity score for predicting the deleteriousness of non-coding regulatory mutations, - the REMM score. -- It is now possible to specify which pathogenicity score or scores you wish to be run out of, polyphen, SIFT, Mutation Taster, - CADD and REMM + reduced memory requirements which is especially handy for genome-sized analyses. +- Exomiser now ships with a new pathogenicity score for predicting the deleteriousness of non-coding regulatory + mutations, + the REMM score. +- It is now possible to specify which pathogenicity score or scores you wish to be run out of, polyphen, SIFT, Mutation + Taster, + CADD and REMM - We now include the variant frequencies from the ExAC dataset and allow for a subset of all frequency sources to be -specified in an analysis. For example, this allows only frequencies from a particular population to be taken into account. + specified in an analysis. For example, this allows only frequencies from a particular population to be taken into + account. ## 6.0.0 2015-01-12 + - Added 'none' type prioritiser for when you really don't want to run any prioritiser. - Exomiser will now show the help options when no parameters are supplied. - New test settings files for different prioritisers and the batch file. - Changed input parameters these are optional switches: - --remove-path-filter-cutoff to --keep-non-pathogenic - --remove-off-target-syn to --keep-off-target + --remove-path-filter-cutoff to --keep-non-pathogenic + --remove-off-target-syn to --keep-off-target - Renamed somewhat misleading example.settings to template.settings to reflect it's intended use. - TSV output now comes in TSV_GENE and TSV_VARIANT flavours. - Added missing ehcache.xml to the distribution. - Switched PostgreSQL driver to use pgjdbc-ng which allegedly has better performance. -- Consolidated JDBC Connection pool to use HikariCP. - +- Consolidated JDBC Connection pool to use HikariCP. + ## 5.2.0 2014-12-18 + - No changes to exomiser-cli ## 5.1.0 2014-12-12 + - No changes to exomiser-cli ## 5.0.1 2014-11-14 + - No changes to exomiser-cli ## 5.0.0 2014-11-14 -- New filter option --genes-to-keep Allows filtering by Entrez gene ID to keep only those genes specified. -- Added caching options which may significantly increase performance at the expense of memory - see application.properties. -- Changed 'username' in application.properties to 'dbuser' to prevent the current user's username from being used to authenticate against the PostgreSQL database on Windows. + +- New filter option --genes-to-keep Allows filtering by Entrez gene ID to keep only those genes specified. +- Added caching options which may significantly increase performance at the expense of memory - see + application.properties. +- Changed 'username' in application.properties to 'dbuser' to prevent the current user's username from being used to + authenticate against the PostgreSQL database on Windows. - Added missing full-analysis option to test and example.settings - Updated external dependencies - Lots of under the hood changes and increased test coverage in exomiser-core. ## 4.0.1 2014-10-23 + - Fixed bug where OMIM prioritiser did not work when inheritance model was not specified - Adjustment of the exomiser-allspecies algorithm for PPI hits ## 4.0.0 2014-09-19 -- Changed FilterScores to FilterResults to encapsulate the pass/fail , score and filterTypes returned from the filters in various ways previously. -- Changed Filter behaviour to simply return a FilterResult instead of altering the VariantEvaluation in inconsistent ways. + +- Changed FilterScores to FilterResults to encapsulate the pass/fail , score and filterTypes returned from the filters + in various ways previously. +- Changed Filter behaviour to simply return a FilterResult instead of altering the VariantEvaluation in inconsistent + ways. - VariantEvaluation now hides a bit more of its inner workings regarding FilterResults. -- PathogenicityData will now return its own most pathogenic score instead of relying on something else to figure this out. +- PathogenicityData will now return its own most pathogenic score instead of relying on something else to figure this + out. -- Major changes to PathogenicityFilter behaviour - Missense variants will always pass the filter regardless of their predicted pathogenicity. Other variant types can now be filtered according to the cutoff score or allowed to pass irrespective of the score. +- Major changes to PathogenicityFilter behaviour - Missense variants will always pass the filter regardless of their + predicted pathogenicity. Other variant types can now be filtered according to the cutoff score or allowed to pass + irrespective of the score. - Command line option changes: - -P --remove-path-filter-cutoff command line option added to allow all variant types through pathogenicity filter. - -P --keep-non-pathogenic-missense command line option removed. - -P option default changed from true to false! Sorry. Check your existing settings carefully! + -P --remove-path-filter-cutoff command line option added to allow all variant types through pathogenicity filter. + -P --keep-non-pathogenic-missense command line option removed. + -P option default changed from true to false! Sorry. Check your existing settings carefully! - Added GeneFilter functionality - Renamed Scorable interface to Score - Renamed VariantEvaluation variables and accessor methods: - getFilterScoreMap to getFilterResults to match how it is referred to in the code output. - getFailedFilters to getFailedFilterTypes - passesFilters to passedFilters + getFilterScoreMap to getFilterResults to match how it is referred to in the code output. + getFailedFilters to getFailedFilterTypes + passesFilters to passedFilters - Bug-fixes - Prioritisers now release database connections when finished (affects batch-mode performance) - Inheritance filter now performs correctly in all cases. ## 3.0.2 2014-09-08 + - VCF output now contains original VCF INFO field with exomiser info appended onto this. - Bug-fix for crash when Jannovar found no annotations for a variant. ## 3.0.1 2014-09-04 + - Bug-fix for duplicate variants in Frequency table where the RSID was different. ## 3.0.0 2014-08-22 + - Completely re-worked under the hood code - New extensible API - Simplified command-line usage @@ -293,5 +395,6 @@ specified in an analysis. For example, this allows only frequencies from a parti - Zero-config installation ## 2.1.0 2014-05-06 + - Embedded H2 database or PostgreSQL - Simplified set-up/installation \ No newline at end of file diff --git a/exomiser-core/CHANGELOG.md b/exomiser-core/CHANGELOG.md index ff2282600..f315827b7 100644 --- a/exomiser-core/CHANGELOG.md +++ b/exomiser-core/CHANGELOG.md @@ -1,12 +1,46 @@ # The Exomiser - Core Library Changelog +## 14.1.0 2024-11-14 + +Further updates to ACMG assignment categories, including implementation of a new AcmgSpliceEvidenceAssigner class which +applies PS1, PP3, BP4, BP7 to splice region variants according to ClinGen recommendations for splicing variants +published in +[Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations +from the ClinGen SVI Splicing Subgroup](https://doi.org/10.1016/j.ajhg.2023.06.002). + +New AcmgPVS1EvidenceAssigner handles assignment of PVS1 to loss of function variants according +to [Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion](https://doi.org/10.1002/humu.23626) + +- Added PS1, PM1, PM5, BS1, BS2 categories to ACMG assignments +- Downgraded BP4 to have a maximum of `Supporting` evidence for REVEL scores under 0.290 +- Updated gene constraints to use gnomad v4.1 data +- Deprecate out of date Acmg2015Classifier and Acgs2020Classifier +- Update JannovarSmallVariantAnnotator to remove `MNV` annotations from effects as these were overriding more damaging + functional effects such as STOP_LOSS, STOP_GAIN, SPLICE_DONOR, SPLICE_ACCEPTOR which prevented potential assignment of + PVS1. +- Update Acmg2015EvidenceAssigner to include BS1, BS2 assignments. +- Refactor Acmg2015EvidenceAssigner missense assignment methods into new AcmgMissenseInFrameIndelEvidenceAssigner class. +- Add PP2/BP1 assignments to AcmgMissenseInFrameIndelEvidenceAssigner using GeneStatistics +- Update ClinVarDao with new getGeneStatistics() method. +- Add new GeneStatistics class for handling aggregated ClinVar gene-level variant effect counts. +- Add new AcmgEvidence.parseAcmgEvidence() method. +- Changes to enable SpliceAI PP3 and other splicing-related ACMG assignments. +- Add new AcmgPVS1EvidenceAssigner class to assign PVS1 to loss of function variants +- Add new AcmgMissenseInFrameIndelEvidenceAssigner class to assign PS1, PM1, PM5, PP2, BP1, PP3, BP4 to missense and + inframe indels +- Add new AcmgSpliceEvidenceAssigner class to assign PS1, PP3, BP4, BP7 to splice region variants +- Add new AcmgEvidence.Builder.containsWithEvidence method +- Add @Nullable to PathogenicityData.pathogenicityScore method + ## 14.0.2 2024-09-20 -- Fix for issue #571. This is a bug-fix release to prevent erroneous assignment of `PVS1` to recessive-compatible variants in LOF-tolerant genes. +- Fix for issue [#571](https://github.com/exomiser/Exomiser/issues/571). This is a bug-fix release to prevent erroneous + assignment of `PVS1` to recessive-compatible variants in LOF-tolerant genes. ## 14.0.1 2024-09-03 -- Fix for Issue #565. This is a patch release to prevent a possible ArrayIndexOutOfBoundsException being thrown when outputting the variants TSV file. There are no other changes. +- Fix for Issue [#565](https://github.com/exomiser/Exomiser/issues/565). This is a patch release to prevent a possible + ArrayIndexOutOfBoundsException being thrown when outputting the variants TSV file. There are no other changes. ## 14.0.0 2024-02-29 @@ -17,15 +51,20 @@ This release **requires data version >= 2402** and **Java version >= 17** (the p - Add new ClinVar conflicting evidence counts in HTML output [#535](https://github.com/exomiser/Exomiser/issues/535) - Added PS1, PM1, PM5 categories to ACMG assignments - Updated gene constraints to use gnomad v4.0 data -- TSV genes, TSV variants and VCF outputs will only write to a single file where the possible modes of inheritances are now shown together rather than split across separate files. +- TSV genes, TSV variants and VCF outputs will only write to a single file where the possible modes of inheritances are + now shown together rather than split across separate files. - Altered reporting of InheritanceModeFilter to state that the number shown refers to variants rather than genes. -- Added new `ClinVarDao` and `ClinVarWhiteListReader` to take advantage of the independently upgradeable ClinVar data files. +- Added new `ClinVarDao` and `ClinVarWhiteListReader` to take advantage of the independently upgradeable ClinVar data + files. - The `VariantWhiteList` is now dynamically loaded from the ClinVar data provided in the clinvar.mv.db file - `VariantDataServiceImpl` now requires a `ClinVarDao` -- Fix for issue [#531](https://github.com/exomiser/Exomiser/issues/531) where the `priorityScoreFilter` and `regulatoryFeatureFilter` pass/fail counts were not displayed in the HTML. -- Fix for issue [#534](https://github.com/exomiser/Exomiser/issues/534) where variant frequency and/or pathogenicity annotations are missing in certain run configurations. +- Fix for issue [#531](https://github.com/exomiser/Exomiser/issues/531) where the `priorityScoreFilter` and + `regulatoryFeatureFilter` pass/fail counts were not displayed in the HTML. +- Fix for issue [#534](https://github.com/exomiser/Exomiser/issues/534) where variant frequency and/or pathogenicity + annotations are missing in certain run configurations. New APIs: + - New `AnalysisDurationFormatter` - New `FilterResultsCounter` - New `FilterResultCount` data class @@ -33,34 +72,45 @@ New APIs: - New `FilterRunner.filterCounts()` and `FilterRunner.logFilterResult()` methods - New `Filterable.failedFilter()` method - New `AlleleData` class to encapsulate building AlleleProto.Frequency and AlleleProto.PathogenicityScore instances -- Added new `ClinVarDao` and `ClinVarWhiteListReader` to take advantage of the independently upgradeable ClinVar data files. -- `Frequency` can either be constructed from a percentage frequency or a set of AC, AN, HOM counts. +- Added new `ClinVarDao` and `ClinVarWhiteListReader` to take advantage of the independently upgradeable ClinVar data + files. +- `Frequency` can either be constructed from a percentage frequency or a set of AC, AN, HOM counts. - Added `AlleleProto.AlleleKey alleleKey()` method to `Variant` to memoise - Add PathogenicitySource `ALPHA_MISSENSE`, `EVE`, `SPLICE_AI` -- Add new `Frequency`, `FrequencySource`, `PathogenicityScore`, `PathogenicitySource`, `VariantEffect` and `ClinVar.ReviewStatus` to proto schema. +- Add new `Frequency`, `FrequencySource`, `PathogenicityScore`, `PathogenicitySource`, `VariantEffect` and + `ClinVar.ReviewStatus` to proto schema. API breaking changes: -- `PathogenicityData` and `FrequencyData` now follow a 'record' rather than 'java bean' pattern for field accessors e.g. `PathogenicityData.clinVarData()` rather than `PathogenicityData.getClinVarData()` + +- `PathogenicityData` and `FrequencyData` now follow a 'record' rather than 'java bean' pattern for field accessors e.g. + `PathogenicityData.clinVarData()` rather than `PathogenicityData.getClinVarData()` - Deleted deprecated `TsvGeneAllMoiResultsWriter`, `TsvVariantAllMoiResultsWriter` and `VcfAllMoiResultsWriter` classes - Delete PathogenicitySource `M_CAP`, `MPC`, `PRIMATE_AI` - Alter ESP FrequencySource long forms to short e.g. `ESP_AFRICAN_AMERICAN` to `ESP_AA` -- TSV output column `CLINVAR_ALLELE_ID` has been changed to `CLINVAR_VARIANT_ID` to allow easier reference to ClinVar variants. - +- TSV output column `CLINVAR_ALLELE_ID` has been changed to `CLINVAR_VARIANT_ID` to allow easier reference to ClinVar + variants. Other changes: + - Updated Spring Boot to version 3.2.3 ## 13.3.0 2023-10-17 -- Updated Jannovar version to 0.41 to fix incorrect MT codon table usage [#521](https://github.com/exomiser/Exomiser/issues/521) -- Downgraded PM2 - PM2_Supporting for variants lacking frequency information [#502](https://github.com/exomiser/Exomiser/issues/502). -- Updated Acgs2020Classifier and Acmg2015Classifier to allow for PVS1 and PM2_Supporting to be sufficient to trigger LIKELY_PATHOGENIC +- Updated Jannovar version to 0.41 to fix incorrect MT codon table + usage [#521](https://github.com/exomiser/Exomiser/issues/521) +- Downgraded PM2 - PM2_Supporting for variants lacking frequency + information [#502](https://github.com/exomiser/Exomiser/issues/502). +- Updated Acgs2020Classifier and Acmg2015Classifier to allow for PVS1 and PM2_Supporting to be sufficient to trigger + LIKELY_PATHOGENIC - Updated AcmgEvidence to fit a Bayesian points-based system [#514](https://github.com/exomiser/Exomiser/issues/514) -- Removed ASJ, FIN, OTH ExAC and gnomAD populations from presets and examples [#513](https://github.com/exomiser/Exomiser/issues/513). -- Fix for regression causing `` variants to be incorrectly down-ranked -- Fix for issue [#486](https://github.com/exomiser/Exomiser/issues/486) where VCF output includes whitespace in INFO field. +- Removed ASJ, FIN, OTH ExAC and gnomAD populations from presets and + examples [#513](https://github.com/exomiser/Exomiser/issues/513). +- Fix for regression causing `` variants to be incorrectly down-ranked +- Fix for issue [#486](https://github.com/exomiser/Exomiser/issues/486) where VCF output includes whitespace in INFO + field. - Logs will now display elapsed time correctly if an analysis runs over an hour (!). -- Updated exomiser-phenotype-data to take annotations from phenotype.hpoa [#351](https://github.com/exomiser/Exomiser/issues/351), [#373](https://github.com/exomiser/Exomiser/issues/373), [#379](https://github.com/exomiser/Exomiser/issues/379) +- Updated exomiser-phenotype-data to take annotations from + phenotype.hpoa [#351](https://github.com/exomiser/Exomiser/issues/351), [#373](https://github.com/exomiser/Exomiser/issues/373), [#379](https://github.com/exomiser/Exomiser/issues/379) - Updated application.properties and ResourceConfigurationProperties to remove unused fields. - Updated DiseaseInheritanceCacheReader and DiseasePhenotypeReader to parse phenotype.hpoa file - Updated DiseaseResourceConfig to use hpoa resource @@ -76,42 +126,46 @@ New APIs: ## 13.2.1 2023-06-30 -- Fix for bug where all `` structural variants were given a maximal variant score of 1.0 regardless of their position on a transcript. -- Added partial implementation of [SVanna scoring](https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01046-6/tables/1) for coding and splice site symbolic variants. -- Fix for issue #481 where TSV and VCF results files would contain no data when the analysis `inheritanceModes` was empty. +- Fix for bug where all `` structural variants were given a maximal variant score of 1.0 regardless of their + position on a transcript. +- Added partial implementation + of [SVanna scoring](https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01046-6/tables/1) for coding + and splice site symbolic variants. +- Fix for issue #481 where TSV and VCF results files would contain no data when the analysis `inheritanceModes` was + empty. -**IMPORTANT!** *This will be the last major release to run on Java 11. Subsequent major releases (i.e. 14+) will require Java 17.* +**IMPORTANT!** *This will be the last major release to run on Java 11. Subsequent major releases (i.e. 14+) will require +Java 17.* ## 13.2.0 2023-02-28 - Fixed excessive CPU usage and application hang after variant prioritisation with large number of results -- Fixed issue [#478](https://github.com/exomiser/Exomiser/issues/478) where gene.tsv output files are empty when running a phenotype only prioritisation. -- Fixed broken links to OMIM in the phenotypic similarity section of the HTML output [#465](https://github.com/exomiser/Exomiser/issues/465) +- Fixed issue [#478](https://github.com/exomiser/Exomiser/issues/478) where gene.tsv output files are empty when running + a phenotype only prioritisation. +- Fixed broken links to OMIM in the phenotypic similarity section of the HTML + output [#465](https://github.com/exomiser/Exomiser/issues/465) - Added gene symbol as HTML id tag in gene panel HTML results [#422](https://github.com/exomiser/Exomiser/pull/422) -- Fixed broken build due to missing sonumina repository and related artefacts [#460](https://github.com/exomiser/Exomiser/issues/460) - +- Fixed broken build due to missing sonumina repository and related + artefacts [#460](https://github.com/exomiser/Exomiser/issues/460) API breaking changes: - None - New APIs: - New `OutputSettings.getOutputDirectory()` - New `OutputSettings.getOutputFileName()` - Deprecated methods: -- `OutputSettings.getOutputPrefix()` deprecated in favour of new `OutputSettings.getOutputDirectory()` and `OutputSettings.getOutputFileName()` methods - +- `OutputSettings.getOutputPrefix()` deprecated in favour of new `OutputSettings.getOutputDirectory()` and + `OutputSettings.getOutputFileName()` methods Other changes: - Update Spring boot 2.6.9 -> 2.7.7 - ## 13.1.0 2022-07-29 The three new features for this release is the automated ACMG classification of small sequence variants, calculating @@ -120,8 +174,10 @@ p-values for the combined scores and providing new and more interpretable TSV an - Added new automated ACMG annotations for top-scoring variants in known disease-causing genes. - Added new combined score p-value - Added new TSV_GENE, TSV_VARIANT and VCF output files containing ranked genes/variants for all the assessed modes of - inheritance. Note that __these new file formats will supersede the existing individual MOI-specific TSV/VCF files which - will be removed in the next major release__. See the [online documentation](https://exomiser.readthedocs.io/en/latest/result_interpretation.html) for details. + inheritance. Note that __these new file formats will supersede the existing individual MOI-specific TSV/VCF files + which + will be removed in the next major release__. See + the [online documentation](https://exomiser.readthedocs.io/en/latest/result_interpretation.html) for details. - New update online documentation! See https://exomiser.readthedocs.io/en/latest/ API breaking changes: @@ -147,14 +203,13 @@ New APIs: - New `TsvVariantAllMoiResultsWriter` - New `VcfAllMoiResultsWriter` - Other changes: + - Updated Spring Boot to version 2.6.9 - Added automated docker build for CLI and web - Update HtmlResultsWriter to detect transcript data source - Fix broken StringDB links in HTML output - ## 13.0.0 2021-09-21 This release is primarily focussed on enabling simultaneous prioritisation of structural and non-structural variation @@ -312,6 +367,7 @@ Other changes: commercial use. ## 11.0.0 2018-09-21 + API breaking changes: - Removed unused `VariantSerialiser` @@ -379,6 +435,7 @@ Other changes: - Updated HTSJDK library to fix `TribbleException` being thrown when trying to parse bgzipped VCF files ## 10.0.0 2018-03-07 + API breaking changes: - Removed previously deprecated `Settings` and `SettingsParser` classes - this was only used by the cli which was also @@ -433,9 +490,11 @@ Other changes: web templates ## 9.0.1 2018-01-15 + - Updated the Jannovar library to 0.24 which now enables filtering for mitochondrial inheritance modes. ## 9.0.0 2017-12-12 + In addition to the user-facing changes listed on the cli, the core has received extensive refactoring and changes. - Maven groupId changed from root `org.monarchinitiative` to more specific `org.monarchinitiative.exomiser`. @@ -456,6 +515,7 @@ In addition to the user-facing changes listed on the cli, the core has received - Updated classes in `analysis` package to enable analyses with user-defined genome assemblies. ## 8.0.0 2017-08-08 + In addition to the user-facing changes listed on the cli, the core has received extensive refactoring and changes. - Namespace changed from `de.charite.compbio` to `org.monarchinitiative`. @@ -472,45 +532,61 @@ In addition to the user-facing changes listed on the cli, the core has received - New `AllelePosition` class for storing POS, REF and ALT and also providing basic variant normalisation/trimming. - New `TabixDataSource` interface to abstract the `TabixReader` allowing simpler testing and other benefits. - -## 7.2.3 2016-11-02 -- Partial bug-fix for multi-sample VCF files where the proband sample is not the first sample in the genotypes section leading to occasional scores of 0 for the exomiser_gene_variant_score in cases where the variants are heterozygous and consistent with autosomal recessive. +## 7.2.3 2016-11-02 + +- Partial bug-fix for multi-sample VCF files where the proband sample is not the first sample in the genotypes section + leading to occasional scores of 0 for the exomiser_gene_variant_score in cases where the variants are heterozygous and + consistent with autosomal recessive. + +*IMPORTANT!* As a workaround for this issue ensure the proband sample is the first sample in the VCF file. This will be +properly fixed in the next major release. -*IMPORTANT!* As a workaround for this issue ensure the proband sample is the first sample in the VCF file. This will be properly fixed in the next major release. +## 7.2.2 2016-07-01 -## 7.2.2 2016-07-01 -- Fix for issue when using OmimPrioritiser with UNDEFINED inheritance mode which led to gene phenotype scores being halved. -- Fix for VCF output multiple allele line duplications. VCF output will now have alternate alleles written out on the same line if they were originally like that in the input VCF. The variant scores will be concatenated to correspond with the alleles. VCFs containing alleles split onto seperate lines in the input file will continue to have them like this in the output file. +- Fix for issue when using OmimPrioritiser with UNDEFINED inheritance mode which led to gene phenotype scores being + halved. +- Fix for VCF output multiple allele line duplications. VCF output will now have alternate alleles written out on the + same line if they were originally like that in the input VCF. The variant scores will be concatenated to correspond + with the alleles. VCFs containing alleles split onto seperate lines in the input file will continue to have them like + this in the output file. ## 7.2.1 2016-01-05 -- Fix for incorrect inheritance mode calculations where the variant chromosome number is prefixed with 'chr' in VCF file. + +- Fix for incorrect inheritance mode calculations where the variant chromosome number is prefixed with 'chr' in VCF + file. ## 7.2.0 2015-11-25 + - Enabled TAD code in AbstractAnalysisRunner - Added isNonCodingVariant() method to Variant interface. - Deprecated VariantAnnotator and VariantFactory constructor which used this. - Added new constructor for VariantFactory which takes a JannovarData object. -- Substantial tidy-up of test helper code with help of new TestFactory, GeneTranscripModelBuilder and VariantContextBuilder classes. +- Substantial tidy-up of test helper code with help of new TestFactory, GeneTranscripModelBuilder and + VariantContextBuilder classes. ## 7.1.0 2015-10-21 + - Added new ChromosomalRegion interface implemented by TopologicalDomain and RegulatoryRegion classes. - Added new ChromosomalRegionIndex class for providing extremely fast lookups of variants in ChromosomalRegions. - Removed RegulatoryFilterDataProvider - this functionality is now in the AbstractAnalysisRunner. ## 7.0.0 2015-10-01 + Now requires Java 8 or higher to run. + - API changes: - New analysis package contains all high-level concepts for analysing exome/genome data - Main Exomiser entry point now accepts an Analysis instead of a SampleData and Settings - ExomiserSettings has been renamed to simply Settings and moved to the analysis package, to use these they should - be converted by the SettingsParser and the resulting Analysis used in the Exomiser. These will run the Exomiser in - the original exome-analysis algorithm, but this is not suitable to genome analysis. + be converted by the SettingsParser and the resulting Analysis used in the Exomiser. These will run the Exomiser in + the original exome-analysis algorithm, but this is not suitable to genome analysis. - An Analysis can be specified either programmatically, or via YAML and read by the AnalysisParser - An Analysis can run in FULL, SPARSE or a new PASS_ONLY mode. The latter is much more memory efficient as it will - only keep those variants/genes which passed all the required filters. + only keep those variants/genes which passed all the required filters. - and a LOT more under the hood changes and clean-ups. ## 6.0.0 2015-01-12 + - API changes: - Package tidy-up - all packages are now use their maven package name as the root package for that project. - PhenixPriority now dies immediately and with an informative message if no HPO terms are supplied. @@ -526,27 +602,32 @@ Now requires Java 8 or higher to run. - Refactored ExomeWalkerPriority and ExomiserAllSpeciesPriority to use new DataMatrix methods. ## 5.2.0 2014-12-18 + - New style HTML output ## 5.1.0 2014-12-12 + - Added ability for the VariantEvaluation to report whether the Variant it is associated with has been annotated by -Jannovar. + Jannovar. - VCF output format will now indicate which, if any variants have not been annotated by Jannovar for whatever reason. - VariantEvaluation can now report a FilterStatus to indicate whether it has passed, failed or is unfiltered. - Further under the hood clean-ups and improved test coverage - now at ~30% ## 5.0.1 2014-11-14 + - Changed Jannovar to version 0.9 to fix a null pointer caused by inability to translate certain variants. ## 5.0.0 2014-11-14 + - Focused on improving test coverage of the Factory and DAO packages in particular. - API changes: - - FrequencyDao and PathogenicityDao are now interfaces implemented by DefaultFrequencyDao and DefaultPathogenicityDao + - FrequencyDao and PathogenicityDao are now interfaces implemented by DefaultFrequencyDao and + DefaultPathogenicityDao - New PedigreeFactory split out of SampleDataFactory - GeneFactory is no longer a static class - VariantEvaluationDataFactory renamed to VariantVariantEvaluationDataService - Removed unused constructors from SampleData - Added getEntrezGeneID method to VariantEvaluation to make API more consistent and lessen direct dependency on - Jannovar Variant in the rest of the code. + Jannovar Variant in the rest of the code. - Removed unused PhredScore class - FilterFactory now returns more specific Filter types - VariantFilter and GeneFilter from the relevant methods