A deep catalogue of protein-coding variation in 983,578 individuals
Authors: Sun Kathie Y. , Bai Xiaodong , Chen Siying , Bao Suying , Zhang Chuanyi , Kapoor Manav , Backman Joshua , Joseph Tyler , Maxwell Evan , Mitra George , Gorovits Alexander , Mansfield Adam , Boutkov Boris , Gokhale Sujit , Habegger Lukas , Marcketta Anthony , Locke Adam E. , Ganel Liron , Hawes Alicia , Kessler Michael D. , Sharma Deepika , Staples Jeffrey , Bovijn Jonas , Gelfman Sahar , Di Gioia Alessandro , Rajagopal Veera M. , Lopez Alexander , Varela Jennifer Rico , Alegre-Díaz Jesús , Berumen Jaime , Tapia-Conyer Roberto , Kuri-Morales Pablo , Torres Jason , Emberson Jonathan , Collins Rory ,   Regeneron Genetics Center,   RGC Management and Leadership Team, Abecasis Gonçalo , Coppola Giovanni , Deubler Andrew , Economides Aris , Ferrando Adolfo , Lotta Luca A. , Shuldiner Alan , Siminovitch Katherine ,   Sequencing and Lab Operations, Beechert Christina , Brian Erin D. , Cremona Laura M. , Du Hang , Forsythe Caitlin , Gu Zhenhua , Guevara Kristy , Lattari Michael , Manoochehri Kia , Challa Prathyusha , Pradhan Manasi , Reynoso Raymond , Schiavo Ricardo , Padilla Maria Sotiropoulos , Wang Chenggu , Wolf Sarah E. ,   Clinical Informatics, Averitt Amelia , Banerjee Nilanjana , Li Dadong , Malhotra Sameer , Mower Justin , Sarwar Mudasar , Staples Jeffrey C. , Yu Sean , Zhang Aaron ,   Genome Informatics and Data Engineering, Bunyea Andrew , Punuru Krishna Pawan , Sreeram Sanjay , Eom Gisu , Sultan Benjamin , Lanche Rouel , Mahajan Vrushali , Austin Eliot , O’Keeffe Sean , Panea Razvan , Polanco Tommy , Rasool Ayesha , Zhang Lance , Edelstein Evan , Guan Ju , Krasheninina Olga , Zarate Samantha , Mansfield Adam J. , Maxwell Evan K. , Sun Kathie ,   Analytical Genetics and Data Science, Ferreira Manuel Allen Revez , Burch Kathy , Campos Adrian , Chen Lei , Choi Sam , Damask Amy , Gaynor Sheila , Geraghty Benjamin , Ghosh Arkopravo , Martinez Salvador Romero , Gillies Christopher , Gurski Lauren , Herman Joseph , Jorgenson Eric , Kessler Michael , Kosmicki Jack , Lin Nan , Locke Adam , Nakka Priyanka , Landheer Karl , Delaneau Olivier , Ghoussaini Maya , Mbatchou Joelle , Moscati Arden , Pandey Aditeya , Pandit Anita , Paulding Charles , Ross Jonathan , Sidore Carlo , Stahl Eli , Suciu Maria , VandeHaar Peter , Vedantam Sailaja , Vrieze Scott , Zhang Jingning , Wang Rujin , Wu Kuan-Han , Ye Bin , Zhang Blair , Ziyatdinov Andrey , Zou Yuxin , Watanabe Kyoko , Tang Mira ,   Therapeutic Area Genetics, Hobbs Brian , Silver Jon , Palmer William , Guerreiro Rita , Joshi Amit , Baldassari Antoine , Willer Cristen , Graham Sarah , Mayerhofer Ernst , Haas Mary , Verweij Niek , Hindy George , De Tanima , Akbari Parsa , Sun Luanluan , Sosina Olukayode , Gilly Arthur , Dornbos Peter , Rodriguez-Flores Juan , Riaz Moeen , Tzoneva Gannie , Jallow Momodou W. , Alkelai Anna , Ayer Ariane , Rajagopal Veera , Kumar Vijay , Otto Jacqueline , Parikshak Neelroop , Guvenek Aysegul , Bras Jose , Alvarez Silvia , Brown Jessie , He Jing , Khiabanian Hossein , Revez Joana , Skead Kimberly , Zavala Valentina ,   Research Program Management and Strategic Initiatives, Mitnaul Lyndon J. , Jones Marcus B. , Chen Esteban , LeBlanc Michelle G. , Mighty Jason , Nishtala Nirupama , Rana Nadia , Rico-Varela Jennifer , Hernandez Jaimee ,   Senior Partnerships and Business Operations, Fenney Alison , Schwartz Randi , Hankins Jody , Hart Samuel ,   Business Operations and Administrative Coordinators, Perez-Beals Ann , Solari Gina , Rivera-Picart Johannie , Pagan Michelle , Siceron Sunilbe ,   RGC-ME Cohort Partners,   Accelerated Cures, Gwynne David ,   African Descent and Glaucoma Evaluation Study (ADAGES) III, Rotter Jerome I. , Weinreb Robert ,   Age-related macular degeneration in the Amish, Haines Jonathan L. , Pericak-Vance Margaret A. , Stambolian Dwight ,   Albert Einstein College of Medicine, Barzilai Nir , Suh Yousin , Zhang Zhengdong ,   Amish Connectome Project, Hong Elliot ,   Amish Research Clinic, Mitchell Braxton ,   The Australia and New Zealand MS Genetics Consortium, Blackburn Nicholas B. , Broadley Simon , Fabis-Pedrini Marzena J. , Jokubaitis Vilija G. , Kermode Allan G. , Kilpatrick Trevor J. , Lechner-Scott Jeanette , Leslie Stephen , McComish Bennet J. , Motyer Allan , Parnell Grant P. , Scott Rodney J. , Taylor Bruce V. , Rubio Justin P. ,   Center for Non-Communicable Diseases (CNCD), Saleheen Danish ,   Cincinnati Children’s Hospital, Kaufman Ken , Kottyan Leah , Martin Lisa , Rothenberg Marc E. ,   Columbia University, Ali Abdullah , Raza Azra ,   Dallas Heart Study, Cohen Jonathan ,   Diabetic Retinopathy Clinical Research (DRCR) Retina Network, Glassman Adam ,   Duke University, Kraus William E. , Newgard Christopher B. , Shah Svati H. ,   Flinders University of South Australia, Craig Jamie , Hewitt Alex ,   Indiana Biobank, Chalasani Naga , Foroud Tatiana , Liangpunsakul Suthat ,   Indiana University School of Medicine, Cox Nancy J. , Dolan Eileen , El-Charif Omar , Travis Lois B. , Wheeler Heather , Gamazon Eric ,   Kaiser Permanente, Sakoda Lori , Witte John ,   Mayo Clinic, Lazaridis Kostantinos ,   Mexico City Prospective Study (MCPS),   MyCode-DiscovEHR Geisinger Health System Biobank, Buchanan Adam , Carey David J. , Martin Christa L. , Meyer Michelle N. , Retterer Kyle , Rolston David ,   National Institute of Mental Health, Akula Nirmala , Besançon Emily , Detera-Wadleigh Sevilla D. , Kassem Layla , McMahon Francis J. , Schulze Thomas G. ,   Northwestern University, Gordon Adam , Smith Maureen , Varga John ,   Penn Medicine Biobank, Bradford Yuki , Damrauer Scott , DerOhannessian Stephanie , Drivas Theodore , Dudek Scott , Dunn Joseph , Haubein Ned , Judy Renae , Ko Yi-An , Kripke Colleen Morse , Livingstone Meghan , Naseer Nawar , Nerz Kyle P. , Poindexter Afiya , Risman Marjorie , Santos Salma , Sirugo Giorgio , Stephanowski Julia , Tran Teo , Vadivieso Fred , Verma Anurag , Verma Shefali S. , Weaver JoEllen , Wollack Colin , Rader Daniel J. , Ritchie Marylyn ,   Primary Open-Angle African American Glaucoma Genetics (POAAG) study, O’Brien Joan ,   Regeneron–Mt. Sinai BioMe Biobank, Bottinger Erwin , Cho Judy ,   UAB GWAS in African Americans with rheumatoid arthritis, Bridges S. Louis ,   UAB Whole exome sequencing of systemic lupus erythematosus patients, Kimberly Robert ,   University of California, Los Angeles, Fejzo Marlena ,   University of Colorado School of Medicine, Spritz Richard A. ,   University of Michigan Medical School, Elder James T. , Nair Rajan P. , Stuart Philip , Tsoi Lam C. ,   University of Ottawa, Dent Robert , McPherson Ruth ,   University of Pennsylvania, Keating Brendan ,   University of Pittsburgh, Kershaw Erin E. , Papachristou Georgios , Whitcomb David C. ,   University of Texas Health Science Center at Houston, Assassi Shervin , Mayes Maureen D. ,   Vanderbilt University Medical Center, Austin Eric D. , Cantor Michael , Thornton Timothy , Kang Hyun Min , Overton John D. , Shuldiner Alan R. , Cremona M. Laura , Nafde Mona , Baras Aris , Abecasis Gonçalo , Marchini Jonathan , Reid Jeffrey G. , Salerno William , Balasubramanian Suganthi 
Published: May 2024

AbstractRare coding variants that substantially affect function provide insights into the biology of a gene1–3. However, ascertaining the frequency of such variants requires large sample sizes4–8. 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.