ArticleEuropean journal of human genetics : EJHG2016
Improving the in silico assessment of pathogenicity for compensated variants.
Article in European journal of human genetics : EJHG, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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Who cites it
17 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Meta-analysis of 46,000 germline de novo mutations linked to human inherited disease.Human genomics · 2024Pooled it
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- Genetic variants in the CD59 gene: An exploratory study of large genome databases.Transfusion · 2025Article
- Pharmacovariome scanning using whole pharmacogene resequencing coupled with deep computational analysis and machine learning for clinical pharmacogenomics.Human genomics · 2023Article
- From bugs to bedside: functional annotation of human genetic variation for neurological disorders using invertebrate models.Human molecular genetics · 2022Article
- Interpreting protein variant effects with computational predictors and deep mutational scanning.Disease models & mechanisms · 2022Review
- Compensatory epistasis explored by molecular dynamics simulations.Human genetics · 2021Article
- Pathogenic missense protein variants affect different functional pathways and proteomic features than healthy population variants.PLoS biology · 2021Article
- MitImpact 3: modeling the residue interaction network of the Respiratory Chain subunits.Nucleic acids research · 2021Article
- Variation benchmark datasets: update, criteria, quality and applications.Database : the journal of biological databases and curation · 2020Article
- Essential genetic findings in neurodevelopmental disorders.Human genomics · 2019Review
- Disease-Associated Genetic Variation in Human Mitochondrial Protein Import.American journal of human genetics · 2019Review
- Interaction of germline variants in a family with a history of early-onset clear cell renal cell carcinoma.Molecular genetics & genomic medicine · 2019Article
- Expanding the clinical phenotype of IARS2-related mitochondrial disease.BMC medical genetics · 2018Article
- The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.Human genetics · 2017Review
- Variants in congenital hypogonadotrophic hypogonadism genes identified in an Indonesian cohort of 46,XY under-virilised boys.Human genomics · 2017Article
- DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously.Frontiers in molecular biosciences · 2017Review
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Understanding the functional sequelae of amino-acid replacements is of fundamental importance in medical genetics. Perhaps, the most intuitive way to assess the potential pathogenicity of a given human missense variant is by measuring the degree of evolutionary conservation of the substituted amino-acid residue, a feature that generally serves as a good proxy metric for the functional/structural importance of that residue. However, the presence of putatively compensated variants as the wild-type alleles in orthologous proteins of other mammalian species not only challenges this classical view of amino-acid essentiality but also precludes the accurate evaluation of the functional impact of this type of missense variant using currently available bioinformatic prediction tools. Compensated variants constitute at least 4% of all known missense variants causing human-inherited disease and hence represent an important potential source of error in that they are likely to be disproportionately misclassified as benign variants. The consequent under-reporting of compensated variants is exacerbated in the context of next-generation sequencing where their inappropriate exclusion constitutes an unfortunate natural consequence of the filtering and prioritization of the very large number of variants generated. Here we demonstrate the reduced performance of currently available pathogenicity prediction tools when applied to compensated variants and propose an alternative machine-learning approach to assess likely pathogenicity for this particular type of variant.
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