[en] Synonymous single nucleotide variants (sSNVs), traditionally seen as neutral, are now recognized for their biological impact. To assess their relevance, we developed SyMetrics, a framework that integrates predictors of splicing, RNA stability, evolutionary conservation, codon usage, synonymous variation effects, sequence properties, and allele frequency. We analyzed all possible sSNVs across the human genome, and our machine-learning model achieved 97% accuracy in distinguishing deleterious from benign variants, with a ROC–AUC of 0.89, outperforming individual predictors. Our estimates indicate that about 1.98 ± 0.17% of sSNVs absent from population databases are damaging (roughly 900 000 sSNVs), with an odds ratio of 3.87 for deleteriousness compared to common sSNVs (P < 0.05). To validate predictions, we performed functional assays on selected sSNVs in the AVPR2 gene and additionally used available large scale mutagenesis screens of RAD51C and BAP1 variants. In a clinical cohort, we identified 15 predicted deleterious sSNVs in genes linked to patient phenotypes; 9 were classified as (likely) pathogenic while 6 were variants of uncertain significance (VUS) per American College of Medical Genetics guidelines. For three VUS, segregation data supported their suspected inheritance patterns (de novo, X-linked). Our findings underscore the functional importance of sSNVs. To support further research and clinical applications, we provide a Python package and web application (https://symetrics.org/) for evaluating these variants comprehensively.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Bundalian, Linnaeus ; Institute of Human Genetics, University of Leipzig Medical Center , Leipzig, Saxony 04103 , ; Institute for Clinical Genetics, Technische Universität Dresden, and National Cancer Center (NCT) Dresden , Dresden, Saxony 01307 ,
Strnadová, Martina Schmidt; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig, Saxony 04103 ,
Garten, Felix; Institute of Human Genetics, University of Leipzig Medical Center , Leipzig, Saxony 04103 ,
Horn, Susanne ; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig, Saxony 04103 ,
Stenzel, Udo; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig, Saxony 04103 ,
Popp, Denny; Institute of Human Genetics, University of Leipzig Medical Center , Leipzig, Saxony 04103 ,
Lemke, Johannes R; Institute of Human Genetics, University of Leipzig Medical Center , Leipzig, Saxony 04103 ,
Garten, Antje; Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig , Leipzig, Saxony 04103 ,
Thor, Doreen; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig, Saxony 04103 ,
Schulz, Angela; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig, Saxony 04103 ,
Hentschel, Julia; Institute of Human Genetics, University of Leipzig Medical Center , Leipzig, Saxony 04103 ,
Kelso, Janet ; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology , Leipzig, Saxony 04103 ,
Schöneberg, Torsten; Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig , Leipzig, Saxony 04103 , ; School of Medicine, University of Global Health Equity , Kigali 6955 ,
Le Duc, Diana ; Institute of Human Genetics, University of Leipzig Medical Center , Leipzig, Saxony 04103 , ; Institute for Clinical Genetics, Technische Universität Dresden, and National Cancer Center (NCT) Dresden , Dresden, Saxony 01307 , ; Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology , Leipzig, Saxony 04103 , ; Center for Diagnostics GmbH, Department of Genetics, Chemnitz Clinics , Chemnitz, Saxony 09116 ,
Else Kroner-Fresenius-Stiftung German Research Foundation Deutsche Forschungsgemeinschaft Deutsche Forschungsgemeinschaft
Funding text :
This study is funded by the Else Kroner-Fresenius-Stiftung 2020_EKEA.42 to D.L.D., the German Research Foundation SFB 1052 project B10 to D.L.D. and A.G, and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1423/2 (project number 421152132) to T.S. and D.T..
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