A deep catalogue of protein-coding variation in 983,578 individuals (2024)

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Abstract Access options Additional access options: Similar content being viewed by others Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis Genome-wide association studies Author information Authors and Affiliations Consortia Regeneron Genetics Center RGC-ME Cohort Partners Corresponding authors Supplementary information Supplementary Information Reporting Summary Supplementary Table 1 Supplementary Table 2 Supplementary Table 3 Supplementary Table 4 Supplementary Table 5 Supplementary Table 6 Supplementary Table 11 Peer Review File Rights and permissions About this article Cite this article Comments

Abstract

Rare coding variants that significantly impact function provide insights into the biology of a gene1-3. However, ascertaining their frequency 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. 23% of the Regeneron Genetics Center Million Exome data (RGC-ME) comes from non-European individuals of African, East Asian, Indigenous American, Middle Eastern, and South Asian ancestry. This catalogue includes over 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, we identify 3,988 loss-of-function intolerant genes, including 86 that were previously assessed as tolerant and 1,153 lacking established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions depleted of missense variants despite being tolerant to 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 important resource of coding variation from the RGC-ME accessible via a public variant allele frequency browser.

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Similar content being viewed by others

A deep catalogue of protein-coding variation in 983,578 individuals (1)

Identifying proteomic risk factors for cancer using prospective and exome analyses of 1463 circulating proteins and risk of 19 cancers in the UK Biobank

Article Open access 15 May 2024

A deep catalogue of protein-coding variation in 983,578 individuals (2)

Analysis of somatic mutations in whole blood from 200,618 individuals identifies pervasive positive selection and novel drivers of clonal hematopoiesis

Article Open access 14 May 2024

A deep catalogue of protein-coding variation in 983,578 individuals (3)

Genome-wide association studies

Article 26 August 2021

Author information

Author notes

  1. These authors contributed equally: Kathie Y. Sun, Xiaodong Bai

Authors and Affiliations

  1. Regeneron Genetics Center, Tarrytown, NY, USA

    Kathie Y. Sun,Xiaodong Bai,Siying Chen,Suying Bao,Chuanyi Zhang,Manav Kapoor,Joshua Backman,Tyler Joseph,Evan Maxwell,George Mitra,Alexander Gorovits,Adam 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,Michael Cantor,Timothy Thornton,Hyun Min Kang,John D. Overton,Alan R. Shuldiner,M. Laura Cremona,Mona Nafde,Aris Baras,Goncalo Abecasis,Jonathan Marchini,Jeffrey G. Reid,William Salerno&Suganthi Balasubramanian

  2. Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico

    Jesus Alegre,Jaime Berumen,Roberto Tapia-Conyer&Pablo Kuri-Morales

  3. Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Mexico

    Pablo Kuri-Morales

  4. Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    Jason Torres,Jonathan Emberson&Rory Collins

Authors

  1. Kathie Y. Sun

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  2. Xiaodong Bai

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  3. Siying Chen

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  4. Suying Bao

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  5. Chuanyi Zhang

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    See Also
    11.1: Eigenvalue Problems for y'' + λy = 0
  6. Manav Kapoor

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  40. Alan R. Shuldiner

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  41. M. Laura Cremona

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  45. Jonathan Marchini

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  46. Jeffrey G. Reid

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  47. William Salerno

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  48. Suganthi Balasubramanian

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Consortia

Regeneron Genetics Center

RGC-ME Cohort Partners

Corresponding authors

Correspondence to William Salerno or Suganthi Balasubramanian.

Supplementary information

Supplementary Information

This Supplementary information file contains the following. Description of Supplementary Tables 1-14. Supplementary Tables 1-6, and 11 are provided as separate data Excel tables. Supplementary Tables 7-10 and 12-14 are embedded within the Supplementary Information document. Supplementary Methods and descriptions of Supplementary Analyses. Supplementary Figures 1-7. Supplementary References.

Supplementary Table 1

This table includes: Sample subsets of RGC-ME used in different analyses; Full breakdown of sample counts in fine-scale ancestry groups used in Fig. 1 and for the browser; and Sample sizes and collaborator details for each dataset in RGC-ME. See main Supplementary Information PDF for full legend.

Supplementary Table 2

shet values for 16,710 genes and other annotations, including additional annotations, LOEUF scores from gnomAD, minor allele frequency, and coding sequence length. See main Supplementary Information PDF for full legend.

Supplementary Table 3

List of continuous segments of missense constrained regions found in 12,349 genes (canonical transcripts), based on the top 15-percentile threshold of MTR values. See main Supplementary Information PDF for full legend.

Supplementary Table 4

Jaccard index analysis between the MTR-constrained regions and features from UniProt (release 2022_05). See main Supplementary Information PDF for full legend.

Supplementary Table 5

List of genes with significant proportion of CDS in top 1, 5, 10, 15, and 20 percentile of exome wide MTR missense constraint scores based on one-sided binomial tests. See main Supplementary Information PDF for full legend.

Supplementary Table 6

List of 4,848 genes with rare (alternate allele frequency <1%) biallelic pLOF variants (hom*ozygous alternate and compound heterozygous) reported for the entire RGC-ME dataset including related individuals. See main Supplementary Information PDF for full legend.

Supplementary Table 11

List of highly differentiated variants (FST > 0.15).

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A deep catalogue of protein-coding variation in 983,578 individuals (4)

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Sun, K.Y., Bai, X., Chen, S. et al. A deep catalogue of protein-coding variation in 983,578 individuals. Nature (2024). https://doi.org/10.1038/s41586-024-07556-0

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  • DOI: https://doi.org/10.1038/s41586-024-07556-0

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A deep catalogue of protein-coding variation in 983,578 individuals (2024)
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