rs74994656
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1
The NM_000245.4(MET):c.2584-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,601,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000093 ( 0 hom. )
Consequence
MET
NM_000245.4 splice_polypyrimidine_tract, intron
NM_000245.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00003673
2
Clinical Significance
Conservation
PhyloP100: 0.309
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 Benign. Variant got -16 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant 7-116769636-T-C is Benign according to our data. Variant chr7-116769636-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 135965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00115 (167/145194) while in subpopulation AFR AF= 0.00384 (149/38770). AF 95% confidence interval is 0.00334. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.2584-9T>C | splice_polypyrimidine_tract_variant, intron_variant | ENST00000397752.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MET | ENST00000397752.8 | c.2584-9T>C | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000245.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00115 AC: 167AN: 145078Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000322 AC: 77AN: 239374Hom.: 0 AF XY: 0.000261 AC XY: 34AN XY: 130390
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GnomAD4 exome AF: 0.0000934 AC: 136AN: 1456128Hom.: 0 Cov.: 35 AF XY: 0.0000856 AC XY: 62AN XY: 724556
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GnomAD4 genome ? AF: 0.00115 AC: 167AN: 145194Hom.: 0 Cov.: 31 AF XY: 0.00115 AC XY: 81AN XY: 70734
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Renal cell carcinoma Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2018 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 20, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at