rs587778446
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The ENST00000397752.8(MET):c.1972G>A(p.Val658Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V658A) has been classified as Likely benign.
Frequency
Consequence
ENST00000397752.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.1972G>A | p.Val658Ile | missense_variant | 8/21 | ENST00000397752.8 | NP_000236.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.1972G>A | p.Val658Ile | missense_variant | 8/21 | 1 | NM_000245.4 | ENSP00000380860 | P3 | |
MET | ENST00000318493.11 | c.1972G>A | p.Val658Ile | missense_variant | 8/21 | 1 | ENSP00000317272 | A2 | ||
MET | ENST00000436117.3 | c.1972G>A | p.Val658Ile | missense_variant, NMD_transcript_variant | 8/20 | 1 | ENSP00000410980 | |||
MET | ENST00000422097.2 | c.1972G>A | p.Val658Ile | missense_variant | 8/12 | 3 | ENSP00000398776 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249324Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135284
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461698Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727144
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74296
ClinVar
Submissions by phenotype
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 20, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 658 of the MET protein (p.Val658Ile). This variant is present in population databases (rs587778446, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 134655). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2024 | Identified in healthy individuals undergoing whole genome sequencing (PMID: 24728327); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24728327) - |
Papillary renal cell carcinoma type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 16, 2019 | 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. - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at