rs796077821
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_000245.4(MET):c.2584-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,600,862 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0013 ( 1 hom., cov: 31)
Exomes 𝑓: 0.0011 ( 3 hom. )
Consequence
MET
NM_000245.4 splice_region, splice_polypyrimidine_tract, intron
NM_000245.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.358
Genes affected
MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP6
?
Variant 7-116769636-TC-T is Benign according to our data. Variant chr7-116769636-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194024.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=4, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00132 (192/145166) while in subpopulation NFE AF= 0.000835 (55/65846). AF 95% confidence interval is 0.000659. There are 1 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.2584-7del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000397752.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.2584-7del | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000245.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00132 AC: 192AN: 145050Hom.: 1 Cov.: 31
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GnomAD4 exome AF: 0.00105 AC: 1531AN: 1455696Hom.: 3 Cov.: 35 AF XY: 0.00105 AC XY: 757AN XY: 724364
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GnomAD4 genome ? AF: 0.00132 AC: 192AN: 145166Hom.: 1 Cov.: 31 AF XY: 0.00127 AC XY: 90AN XY: 70714
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 19, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 03, 2022 | Variant summary: MET c.2638-7delC alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0016 in 239374 control chromosomes. The observed variant frequency is approximately 1050 fold of the estimated maximal expected allele frequency for a pathogenic variant in MET causing Papillary Renal Cell Carcinoma phenotype (1.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2638-7delC in individuals affected with Papillary Renal Cell Carcinoma and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (n=2) and likely benign (n=4). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 28, 2014 | - - |
Renal cell carcinoma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Papillary renal cell carcinoma type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 06, 2020 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at