rs570176656
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5BP4_StrongBP6
The NM_020975.6(RET):c.230G>A(p.Arg77His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,792 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R77C) has been classified as Pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.230G>A | p.Arg77His | missense_variant | 2/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.230G>A | p.Arg77His | missense_variant | 2/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250598Hom.: 0 AF XY: 0.0000664 AC XY: 9AN XY: 135616
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461520Hom.: 1 Cov.: 64 AF XY: 0.0000330 AC XY: 24AN XY: 727062
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74438
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 77 of the RET protein (p.Arg77His). This variant is present in population databases (rs570176656, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 477344). 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 histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Arg77 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10618407, 10982477, 29261189). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2021 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at