Decoding the effects of synonymous variants

Abstract

Synonymous single nucleotide variants (sSNVs) are common in the human genome but are often overlooked. However, sSNVs can have significant biological impact and may lead to disease. Existing computational methods for evaluating the effect of sSNVs suffer from the lack of gold-standard training/evaluation data and exhibit over-reliance on sequence conservation signals. We developed synVep (synonymous Variant effect predictor), a machine learning-based method that overcomes both of these limitations. Our training data was a combination of variants reported by gnomAD (observed) and those unreported, but possible in the human genome (generated). We used positive-unlabeled learning to purify the generated variant set of any likely unobservable variants. We then trained two sequential extreme gradient boosting models to identify subsets of the remaining variants putatively enriched and depleted in effect. Our method attained 90% precision/recall on a previously unseen set of variants. Furthermore, although synVep does not explicitly use conservation, its scores correlated with evolutionary distances between orthologs in cross-species variation analysis. synVep was also able to differentiate pathogenic vs. benign variants, as well as splice-site disrupting variants (SDV) vs. non-SDVs. Thus, synVep provides an important improvement in annotation of sSNVs, allowing users to focus on variants that most likely harbor effects. Availability: synVep webserver for online query: https://services.bromberglab.org/synvep; For local runs Python script (https://bitbucket.org/bromberglab/synvep_local) and prediction database (https://zenodo.org/record/4763256) are also available.

Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2: a case report

“…Synonymous mutations were previously thought to have no functional impact. Growing studies have shown that synonymous mutations affect DNA, RNA, and protein-based features [23][24][25] . The COL11A2 c.3774 C > T is close to the marginal zone of exons, which does not alter the protein sequence and may cause splicing abnormalities [26] .…”