rs77702891
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_020975.6(RET):c.938G>A(p.Arg313Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R313L) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.938G>A | p.Arg313Gln | missense_variant | 5/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.938G>A | p.Arg313Gln | missense_variant | 5/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000121 AC: 30AN: 248534Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 134798
GnomAD4 exome AF: 0.0000287 AC: 42AN: 1461150Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18AN XY: 726842
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2A Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 27, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 15, 2021 | - - |
Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the RET protein (p.Arg313Gln). This variant is present in population databases (rs77702891, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 9090527, 22174939). ClinVar contains an entry for this variant (Variation ID: 13932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2022 | Also reported in a patient with short segment Hirschsprung disease, but it is unknown whether this individual was screened for variants in other genes associated with this phenotype (So et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in the homozygous state in a patient with total colonic aganglionosis with small bowel involvement who underwent targeted testing of the RET gene; both parents of this individual were heterozygous for this variant and were reportedly healthy (Seri et al., 1997); This variant is associated with the following publications: (PMID: 21995290, 9090527, 22174939) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2023 | The p.R313Q variant (also known as c.938G>A), located in coding exon 5 of the RET gene, results from a G to A substitution at nucleotide position 938. The arginine at codon 313 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a homozygous state in a child born to consanguineous parents with the most severe Hirschsprung disease phenotype (total colonic aganglionosis with small bowel involvement) (Seri M et al. Hum. Mutat. 1997;9:243-9). This alteration has also been reported in a cohort of 601 Chinese Hirschsprung disease patients (So MT et al. PLoS One. 2011 Dec;6:e28986). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a multiple endocrine neoplasia type 2 (MEN2) disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. - |
Hirschsprung disease, susceptibility to, 1 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at