ClinVar Genomic variation as it relates to human health

A heterozygous missense variant, NM_017831.3(RNF125):c.24C>G, has been identified in exon 0 of the RNF125 gene. The variant is predicted to result in a minor amino acid change from aspartic acid to glutamic acid at position 8 of the protein (NP_060301.2(RNF125):p.(Asp8Glu)). The aspartic acid residue at this position has low conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In silico predictions for this variant are consistently benign (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.009% (21 heterozygotes, 0 homozygotes). This variant has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN.

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 1806236). This variant has not been reported in the literature in individuals affected with RNF125-related conditions. This variant is present in population databases (rs759640087, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 8 of the RNF125 protein (p.Asp8Glu).

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.