Genome Alert!

Overview

This repository contains the Genome Alert! framework and shiny app https://genomealert.univ-grenoble-alpes.fr/.

Genome Alert! is an automated monitoring and curating method of variant pathogenicity and genotype-phenotype knowledge in ClinVar database.

This app display processed ClinVar data through the Genome Alert! framework :

• ClinVCF monitors submissions and extracts clinical information from a Clinvar XML monthly Full Release into an easy-to-manipulate standard VCF 4.2 file.
  In order to reclassify high confidence pathogenic variants with a conflicting interpretation of pathogenicity status, ClinVCF first removes ACMG classification outliers submissions for variants with at least 4 submissions according to the 1.5 * Interquartile Range method. Secondly, it reclassifies the variant status according to the ClinVar classification system and finally we set the reclassification confidence with a three-tier level system. https://github.com/SeqOne/clinvcf
• Variant Alert! track every significant changes in variant classification and gene-disease association between two versions of ClinVCF VCFs, including their major status defined according to the suspected clinical impact of these changes. A major change is defined as a potential direct impact on clinical diagnosis. A minor change is a change in confidence classification (e.g. Pathogenic to Likely Pathogenic status). https://github.com/SeqOne/variant_alert
• ClinVarome gathers and processes all ClinVar knowledge available through time. Through an unsupervised clustering model, it classifies clinical validity of information for each gene in four clusters https://github.com/SeqOne/clinvarome.

Complete pipeline to generate the overall data

Generate all VCFs from ClinVar data with ClinVCF

First, install ClinVCF and then download all Clinvar XML file

cd OUTPUT_PATH/
wget -r ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/xml/

Copy all file into one folder

mkdir OUTPUT_PATH/data
find OUTPUT_PATH/ftp.ncbi.nlm.nih.gov/ -type f -print0 | xargs -0 cp -t OUTPUT_PATH/data/

Get list to process clinvcf (XML to VCF)

ls OUTPUT_PATH/data/ | grep ".xml.gz" | grep -v "md5" > OUTPUT_PATH/data/clinvar_xml_list.txt

Process all ClinVar XML release with ClinVCF

while read -r line ; do 
  echo line
  echo ${line}
  echo filename
  filename=$(echo "$line" | cut -d. -f1 | cut -d_ -f2) 
  echo ${filename}
  if [ -f "OUTPUT_PATH/data/clinvar_GRCh38_${filename}.vcf.gz" ]
  then
    echo "${filename} already processed"
  else
  clinvcf --genome GRCh38 --coding-first --gff data/GRCh38_latest_genomic.gff OUTPUT_PATH/data/${line} | bgzip -c > OUTPUT_PATH/data/clinvar_GRCh38_${filename}.vcf.gz
  tabix -p vcf OUTPUT_PATH/data/clinvar_GRCh38_${filename}.vcf.gz
  fi
done < OUTPUT_PATH/data/clinvar_xml_list.txt

Process Variant Alert! in whole ClinVar history

Install Variant Alert!.

Launch Variant Alert! environment

cd variant_alert/
poetry shell 

Get GenomeAlert-App.

git clone https://github.com/SeqOne/GenomeAlert-App

Run Variant Alert! for all version and all command (compare-variant, compare-gene and clinvarome)

mkdir OUTPUT_PATH/VA_output/
cd GenomeAlert-App
python variant_alert_execution.py --vcf-path OUTPUT_PATH/data/ --VA-output-path OUTPUT_PATH/VA_output/
gzip OUTPUT_PATH/VA_output/compare-gene_total.tsv
gzip OUTPUT_PATH/VA_output/compare-variant_total.tsv

Get ClinVarome annotated data

Install ClinVarome

Run ClinVarome

cd ClinVarome
poetry run clinvarome/clinvarome_annotation.py \
  --vcf OUTPUT_PATH/data/clinvar_GRCh38_latest.vcf.gz \
  --clinvarome OUTPUT_PATH/VA_output/clinvarome_latest.tsv \
  --compare-gene OUTPUT_PATH/VA_output/compare-gene_total.tsv.gz \
  --compare-variant OUTPUT_PATH/VA_output/compare-variant_total.tsv.gz \
  --output-dir OUTPUT_PATH/VA_output/

Move input file in www folder

cd GenomeAlert-App/
mv OUTPUT_PATH/VA_output/compare-gene_total.tsv.gz www/
mv OUTPUT_PATH/VA_output/compare-variant_total.tsv.gz www/
mv OUTPUT_PATH/VA_output/clinvarome_{latest}.tsv www/

Shiny app installation

Requirements

ubuntu-server
r-base
shiny-server

library(tidyverse)
library(lubridate)
library(shiny)
library(shinythemes)
library(htmlwidgets)
library(markdown)

NB: Installation guide is available in RStudio website.

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Genome Alert! is a collaboration of :