rs758486336
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_000245.4(MET):c.4150G>A(p.Ala1384Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,812 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. A1384G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000245.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.4150G>A | p.Ala1384Thr | missense_variant | 21/21 | ENST00000397752.8 | |
MET | NM_001127500.3 | c.4204G>A | p.Ala1402Thr | missense_variant | 21/21 | ||
MET | NM_001324402.2 | c.2860G>A | p.Ala954Thr | missense_variant | 20/20 | ||
MET | XM_011516223.2 | c.4207G>A | p.Ala1403Thr | missense_variant | 22/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.4150G>A | p.Ala1384Thr | missense_variant | 21/21 | 1 | NM_000245.4 | P3 | |
MET | ENST00000318493.11 | c.4204G>A | p.Ala1402Thr | missense_variant | 21/21 | 1 | A2 | ||
MET | ENST00000436117.3 | c.*1755G>A | 3_prime_UTR_variant, NMD_transcript_variant | 20/20 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249144Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135152
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461812Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727220
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2023 | - - |
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1402 of the MET protein (p.Ala1402Thr). This variant is present in population databases (rs758486336, gnomAD 0.009%). 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: 411906). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 | Feb 01, 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; Observed in an individual with thyroid cancer in published literature (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080) - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2022 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at