Variant interpretation using population databases: lessons from gnomAD

By Sanna Gudmundsson, M. Singer-Berk, N. Watts, W. Phu, J. Goodrich, Matthew Solomonson, G. Consortium, H. Rehm, Daniel G. MacArthur, Anne H. O'Donnell-Luria. Human Mutation, 2021

533 citations recorded by the source corpus.

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.

Subfields: Genetics

View Paper: https://www.semanticscholar.org/paper/d5db5e591db09e3250b1a8c06d739d15d7d1b47e

Citations in the corpus

• Genome-wide prediction of disease variants with a deep protein language model (2022, methodology): “To calculate the ROC-AUC, we considered the entire set of pathogenic and benign variants (either from ClinVar [10] or HGMD/gnomAD [9, 26]) as a single genome-wide classification task, and consecutively calculated the global ROC-AUC of ESM1b and EVE over each of the two datasets ( Fig.”