When a Synonymous Variant Is Nonsynonymous

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.