Here, we describe the joint variant calling and analysis of high-quality variant calls across 60,706 human exomes, assembled by the Exome Aggregation Consortium (ExAC; exac.broadinstitute.org). This call set exceeds previously available exome-wide variant databases by nearly an order of magnitude, providing substantially increased resolution for the analysis of very low-frequency genetic variants. We demonstrate the application of this data set to the analysis of patterns of genetic variation including the discovery of widespread mutational recurrence, the inference of gene-level constraint against truncating variation, the clinical interpretation of variation in Mendelian disease genes, and the discovery of human “knockout” variants in protein-coding genes.
