rs555920594
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000245.4(MET):āc.80A>Gā(p.Lys27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,828 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 Uncertain significance (ā ā ). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.
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.80A>G | p.Lys27Arg | missense_variant | 2/21 | ENST00000397752.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.80A>G | p.Lys27Arg | missense_variant | 2/21 | 1 | NM_000245.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249398Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135298
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727144
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74384
ClinVar
Submissions by phenotype
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 13, 2021 | This variant has not been reported in the literature in individuals with MET-related disease. 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. 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 arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces lysine with arginine at codon 27 of the MET protein (p.Lys27Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 22, 2021 | The p.K27R variant (also known as c.80A>G), located in coding exon 1 of the MET gene, results from an A to G substitution at nucleotide position 80. The lysine at codon 27 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at