Variant interpretation using population databases: lessons from gnomAD.
Sanna GudmundssonMoriel Singer-BerkNicholas A WattsWilliam PhuJulia K GoodrichMatthew SolomonsonGenome Aggregation Database ConsortiumMichael J BamshadDaniel G MacArthurAnne H O'Donnell-LuriaPublished in: Human mutation (2021)
Reference population databases are an essential tool in variant and gene interpretation. Their use guides the identification of pathogenic variants amidst the sea of benign variation present in every human genome, and supports the discovery of new disease-gene relationships. The Genome Aggregation Database (gnomAD) is currently the largest and most widely used publicly available collection of population variation from harmonized sequencing data. The data is available through the online gnomAD browser (https://gnomad.broadinstitute.org/) that enables rapid and intuitive variant analysis. This review provides guidance on the content of the gnomAD browser, and its usage for variant and gene interpretation. We introduce key features including allele frequency, per-base expression levels, constraint scores, and variant co-occurrence, alongside guidance on how to use these in analysis, with a focus on the interpretation of candidate variants and novel genes in rare disease. This article is protected by copyright. All rights reserved.
Keyphrases
- genome wide
- copy number
- genome wide identification
- big data
- dna methylation
- small molecule
- poor prognosis
- endothelial cells
- genome wide analysis
- high throughput
- transcription factor
- single cell
- long non coding rna
- bioinformatics analysis
- machine learning
- induced pluripotent stem cells
- loop mediated isothermal amplification