7-116795993-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000245.4(MET):c.4042C>A(p.His1348Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. H1348H) has been classified as Likely benign.
Frequency
Consequence
NM_000245.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.4042C>A | p.His1348Asn | missense_variant | 21/21 | ENST00000397752.8 | |
MET | NM_001127500.3 | c.4096C>A | p.His1366Asn | missense_variant | 21/21 | ||
MET | NM_001324402.2 | c.2752C>A | p.His918Asn | missense_variant | 20/20 | ||
MET | XM_011516223.2 | c.4099C>A | p.His1367Asn | missense_variant | 22/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.4042C>A | p.His1348Asn | missense_variant | 21/21 | 1 | NM_000245.4 | P3 | |
MET | ENST00000318493.11 | c.4096C>A | p.His1366Asn | missense_variant | 21/21 | 1 | A2 | ||
MET | ENST00000436117.3 | c.*1647C>A | 3_prime_UTR_variant, NMD_transcript_variant | 20/20 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249310Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135254
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461836Hom.: 0 Cov.: 57 AF XY: 0.00000413 AC XY: 3AN XY: 727232
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1366 of the MET protein (p.His1366Asn). This variant is present in population databases (rs773772398, 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: 219692). 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) performed at Invitae indicates that this missense variant is expected to disrupt MET protein function with a positive predictive value of 80%. 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 | Nov 14, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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 | Jul 03, 2023 | The p.H1366N variant (also known as c.4096C>A), located in coding exon 20 of the MET gene, results from a C to A substitution at nucleotide position 4096. The histidine at codon 1366 is replaced by asparagine, an amino acid with similar properties. 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