A deep catalogue of protein-coding variation in 983,578 individuals
Kathie Sun, Xiaodong Bai, Siying Chen, Suying Bao, Chuanyi Zhang, Manav Kapoor, Joshua Backman, Tyler Joseph, Evan K. Maxwell, George Mitra, Alexander Gorovits, Adam J. Mansfield, Boris Boutkov, Sujit Gokhale, Lukas Habegger, Anthony Marcketta, Adam E. Locke, Liron Ganel, Alicia Hawes, Michael D. Kessler, Deepika Sharma, Jeffrey Staples, Jonas Bovijn, Sahar Gelfman, Alessandro Di Gioia, Veera M. Rajagopal, Alexander Lopez, Jennifer Rico Varela, Jesús Alegre-Díaz, Jaime Berúmen, Roberto Tapia‐Conyer, Pablo Kuri‐Morales, Jason Torres, Jonathan Emberson, Rory Collins, RGC Management and Leadership Team, Gonçalo Abecasis, Giovanni Coppola, Andrew Deubler, Aris Economides, Adolfo A. Ferrando, Luca A. Lotta, Alan R. Shuldiner, Katherine Siminovitch, Sequencing and Lab Operations, Christina Beechert, Erin D. Brian, Laura M. Cremona, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Amelia Averitt, Nilanjana Banerjee, Dadong Li, Sameer Malhotra, Justin Mower, Mudasar Sarwar, Jeffrey C. Staples, Sean Yu, Aaron Zhang, Genome Informatics and Data Engineering, Andrew Bunyea, Krishna Pawan Punuru, Sanjay Sreeram, Gisu Eom, Benjamin Sultan, Rouel Lanche, Vrushali Mahajan, Eliot Austin, Sean O’Keeffe, Razvan Panea, Tommy Polanco, Ayesha Rasool, Lance Zhang, Evan Edelstein, Ju Guan, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Evan K. Maxwell, Kathie Sun, Analytical Genetics and Data Science, Manuel Allen Revez Ferreira, Kathy Burch, Adrián I. Campos, Lei Chen, Sam Choi, Amy Damask, Sheila M. Gaynor, Benjamin Geraghty
Abstract
. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.