rs375391602
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000245.4(MET):c.1238G>A(p.Arg413His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. R413S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000245.4 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 |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.1238G>A | p.Arg413His | missense_variant | 3/21 | ENST00000397752.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.1238G>A | p.Arg413His | missense_variant | 3/21 | 1 | NM_000245.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249440Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135330
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461800Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727194
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a history of breast cancer (Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 35264596) - |
Papillary renal cell carcinoma type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2023 | The p.R413H variant (also known as c.1238G>A), located in coding exon 2 of the MET gene, results from a G to A substitution at nucleotide position 1238. The arginine at codon 413 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Renal cell carcinoma Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at