chr10-43100576-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020975.6(RET):c.191C>T(p.Pro64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. P64S) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.191C>T | p.Pro64Leu | missense_variant | 2/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.191C>T | p.Pro64Leu | missense_variant | 2/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 64
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | Experimental studies have shown that this missense change affects RET function (PMID: 8894691). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 13924). This missense change has been observed in individual(s) with Hirschprung disease (PMID: 7581377, 8114939). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 64 of the RET protein (p.Pro64Leu). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 27, 2023 | - - |
Hirschsprung disease, susceptibility to, 1 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jan 27, 1994 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at