rs200690492
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000245.4(MET):c.1019A>G(p.Asp340Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,610,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D340H) has been classified as Uncertain significance.
Frequency
Consequence
NM_000245.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.1019A>G | p.Asp340Gly | missense_variant | 2/21 | ENST00000397752.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.1019A>G | p.Asp340Gly | missense_variant | 2/21 | 1 | NM_000245.4 | P3 | |
MET | ENST00000318493.11 | c.1019A>G | p.Asp340Gly | missense_variant | 2/21 | 1 | A2 | ||
MET | ENST00000436117.3 | c.1019A>G | p.Asp340Gly | missense_variant, NMD_transcript_variant | 2/20 | 1 | |||
MET | ENST00000422097.2 | c.1019A>G | p.Asp340Gly | missense_variant | 2/12 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000814 AC: 2AN: 245790Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133330
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1458096Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 725156
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with atherosclerosis and unspecified cancer history (Johnston 2012); This variant is associated with the following publications: (PMID: 22703879) - |
Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
MET-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2022 | The MET c.1019A>G variant is predicted to result in the amino acid substitution p.Asp340Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-116340157-A-G) and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41608/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 07, 2023 | - - |
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 340 of the MET protein (p.Asp340Gly). This variant is present in population databases (rs200690492, gnomAD 0.003%). 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: 41608). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MET 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2023 | The p.D340G variant (also known as c.1019A>G), located in coding exon 1 of the MET gene, results from an A to G substitution at nucleotide position 1019. The aspartic acid at codon 340 is replaced by glycine, an amino acid with similar properties. This alteration was previously reported as a secondary finding in 1/571 individuals undergoing exome sequencing due to an atherosclerosis phenotype (Johnston et al. Am. J. Hum. Genet. 2012 Jul; 91(1):97-108). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at