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. 2022 Aug 19;13(8):1485.
doi: 10.3390/genes13081485.

When a Synonymous Variant Is Nonsynonymous

Mauno Vihinen  1
Affiliations

When a Synonymous Variant Is Nonsynonymous

Mauno Vihinen. Genes (Basel). .

Abstract

Term synonymous variation is widely used, but frequently in a wrong or misleading meaning and context. Twenty three point eight % of possible nucleotide substitution types in the universal genetic code are for synonymous amino acid changes, but when these variants have a phenotype and functional effect, they are very seldom synonymous. Such variants may manifest changes at DNA, RNA and/or protein levels. Large numbers of variations are erroneously annotated as synonymous, which causes problems e.g., in clinical genetics and diagnosis of diseases. To facilitate precise communication, novel systematics and nomenclature are introduced for variants that when looking only at the genetic code seem like synonymous, but which have phenotypes. A new term, unsense variant is defined as a substitution in the mRNA coding region that affects gene expression and protein production without introducing a stop codon in the variation site. Such variants are common and need to be correctly annotated. Proper naming and annotation are important also to increase awareness of these variants and their consequences.

Keywords: annotation; mutation; synonymous variation; terminology; variation interpretation; variation naming.

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Conflict of interest statement

The author declared no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Types of RNA variations as described in VariO. Substitutions are divided into six categories. Transitions and transversions describe the chemical change of the base group in a nucleotide. Missense, nonsense, synonymous and the new term unsense describe the outcomes of the alterations in relation to translation, splicing, regulation and function.
Figure 2
Figure 2
Novel classification of unsense and synonymous variations, molecular levels where they have functions, their mechanisms, as well as effects. Synonymous variants can affect DNA (red boxes), RNA (white) and protein levels (blue), whereas unsense variants are at RNA level and affect splicing, regulation or binding. PTM, post translational modification.
Figure 3
Figure 3
Types of RNA substitutions and VariO codes, and their definitions.
See this image and copyright information in PMC

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