chr7-116796026-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBP6
The NM_000245.4(MET):c.4075G>A(p.Val1359Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,842 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).
Frequency
Consequence
NM_000245.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.4075G>A | p.Val1359Ile | missense_variant | 21/21 | ENST00000397752.8 | NP_000236.2 | |
MET | NM_001127500.3 | c.4129G>A | p.Val1377Ile | missense_variant | 21/21 | NP_001120972.1 | ||
MET | NM_001324402.2 | c.2785G>A | p.Val929Ile | missense_variant | 20/20 | NP_001311331.1 | ||
MET | XM_011516223.2 | c.4132G>A | p.Val1378Ile | missense_variant | 22/22 | XP_011514525.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.4075G>A | p.Val1359Ile | missense_variant | 21/21 | 1 | NM_000245.4 | ENSP00000380860.3 | ||
MET | ENST00000318493.11 | c.4129G>A | p.Val1377Ile | missense_variant | 21/21 | 1 | ENSP00000317272.6 | |||
MET | ENST00000436117.3 | n.*1680G>A | non_coding_transcript_exon_variant | 20/20 | 1 | ENSP00000410980.2 | ||||
MET | ENST00000436117.3 | n.*1680G>A | 3_prime_UTR_variant | 20/20 | 1 | ENSP00000410980.2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249290Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135242
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461726Hom.: 0 Cov.: 58 AF XY: 0.0000426 AC XY: 31AN XY: 727172
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74294
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 13, 2023 | - - |
Renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 16, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1377 of the MET protein (p.Val1377Ile). This variant is present in population databases (rs752669237, 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: 216510). 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 not expected to disrupt 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Papillary renal cell carcinoma type 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2020 | 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