RT Journal Article SR Electronic T1 Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes JF bioRxiv FD Cold Spring Harbor Laboratory SP 531210 DO 10.1101/531210 A1 Konrad J. Karczewski A1 Laurent C. Francioli A1 Grace Tiao A1 Beryl B. Cummings A1 Jessica Alföldi A1 Qingbo Wang A1 Ryan L. Collins A1 Kristen M. Laricchia A1 Andrea Ganna A1 Daniel P. Birnbaum A1 Laura D. Gauthier A1 Harrison Brand A1 Matthew Solomonson A1 Nicholas A. Watts A1 Daniel Rhodes A1 Moriel Singer-Berk A1 Eleanor G. Seaby A1 Jack A. Kosmicki A1 Raymond K. Walters A1 Katherine Tashman A1 Yossi Farjoun A1 Eric Banks A1 Timothy Poterba A1 Arcturus Wang A1 Cotton Seed A1 Nicola Whiffin A1 Jessica X. Chong A1 Kaitlin E. Samocha A1 Emma Pierce-Hoffman A1 Zachary Zappala A1 Anne H. O’Donnell-Luria A1 Eric Vallabh Minikel A1 Ben Weisburd A1 Monkol Lek A1 James S. Ware A1 Christopher Vittal A1 Irina M. Armean A1 Louis Bergelson A1 Kristian Cibulskis A1 Kristen M. Connolly A1 Miguel Covarrubias A1 Stacey Donnelly A1 Steven Ferriera A1 Stacey Gabriel A1 Jeff Gentry A1 Namrata Gupta A1 Thibault Jeandet A1 Diane Kaplan A1 Christopher Llanwarne A1 Ruchi Munshi A1 Sam Novod A1 Nikelle Petrillo A1 David Roazen A1 Valentin Ruano-Rubio A1 Andrea Saltzman A1 Molly Schleicher A1 Jose Soto A1 Kathleen Tibbetts A1 Charlotte Tolonen A1 Gordon Wade A1 Michael E. Talkowski A1 The Genome Aggregation Database Consortium A1 Benjamin M. Neale A1 Mark J. Daly A1 Daniel G. MacArthur YR 2019 UL http://biorxiv.org/content/early/2019/01/30/531210.abstract AB Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes critical for an organism’s function will be depleted for such variants in natural populations, while non-essential genes will tolerate their accumulation. However, predicted loss-of-function (pLoF) variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes. Here, we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence pLoF variants in this cohort after filtering for sequencing and annotation artifacts. Using an improved model of human mutation, we classify human protein-coding genes along a spectrum representing intolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve gene discovery power for both common and rare diseases.