Regional missense constraint improves variant deleteriousness prediction
Open accessAbstract
Given increasing numbers of patients who are undergoing exome or genome sequencing, it is critical to establish tools and methods to interpret the impact of genetic variation. While the ability to predict deleteriousness for any given variant is limited, missense variants remain a particularly challenging class of variation to interpret, since they can have drastically different effects depending on both the precise location and specific amino acid substitution of the variant. In order to better evaluate missense variation, we leveraged the exome sequencing data of 60,706 individuals from the Exome Aggregation Consortium (ExAC) dataset to identify sub-genic regions that are depleted of missense variation. We further used this depletion as part of a novel missense deleteriousness metric named MPC. We applied MPC to de novo missense variants and identified a category of de novo missense variants with the same impact on neurodevelopmental disorders as truncating mutations in intolerant genes, supporting the value of incorporating regional missense constraint in variant interpretation.
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Using MPC score ≥2, 8% of de novo missense variants are predicted deleterious and are enriched 1.88-fold in affected offspring, comparable with dnLGD enrichment (p-value = 9.9 × 10−4).
“Using a more strict D-mis prediction algorithm with MPC score ≥2,11 8% of de novo missense variants are predicted as deleterious and are enriched 1.88-fold in affected offspring which is comparable with the enrichment of dnLGD variants (p-value = 9.9 × 10−4 by one-sided exact Poisson test).”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [11]
Missense variants and protein-truncating variants differ in their impact on protein function.
“missense variants and protein-truncating variants (PTVs) vary in their impact on protein function3–6.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [4]
Existing methods for detecting gene-specific enrichment of damaging de novo mutations ignore much prior information about which variants are more likely disease-associated.
“Existing methods to detect gene-specific enrichments of damaging DNMs ignore much prior information about which variants are more likely to be disease-associated; missense variants and protein-truncating variants (PTVs) vary in their impact on protein function3–6.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [4]
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Self-citation
- Authors
- Samocha, K. E., Kosmicki, J. A., Karczewski, K. J., O’Donnell-Luria, A. H., Pierce-Hoffman, E., MacArthur, D. G., Neale, B. M., & Daly, M. J.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Daly, Mark J.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2017-06-12
- OpenAlex
- W2625862723
- Cited by
- 351
- References
- 28
- Citations by year
- 2026: 19 · 2025: 42 · 2024: 56 · 2023: 43 · 2022: 47 · 2021: 49 · 2020: 34 · 2019: 40 · 2018: 17 · 2017: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Funders
- National Institute of General Medical Sciences (F32GM115208, T32GM007748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- missense mutations, variant interpretation, de novo mutations, neurodevelopmental disorders, ExAC, truncating mutations
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