rs587780811
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_020975.6(RET):c.2833G>A(p.Val945Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V945A) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2833G>A | p.Val945Met | missense_variant | Exon 17 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251480Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727214
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:2
This missense variant replaces valine with methionine at codon 945 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 945 of the RET protein (p.Val945Met). This variant is present in population databases (rs587780811, gnomAD 0.004%). This missense change has been observed in individual(s) with pediatric cancer (PMID: 34771502). ClinVar contains an entry for this variant (Variation ID: 136113). 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 disruptive. 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 Uncertain:2
- -
The p.V945M variant (also known as c.2833G>A), located in coding exon 17 of the RET gene, results from a G to A substitution at nucleotide position 2833. The valine at codon 945 is replaced by methionine, an amino acid with highly similar properties. 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 MEN2-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. -
Multiple endocrine neoplasia type 2A Uncertain:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at