NM_000245.4:c.2584-7delC
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2
The NM_000245.4(MET):c.2584-7delC variant causes a splice region, 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000245.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MET | NM_000245.4 | c.2584-7delC | splice_region_variant, intron_variant | Intron 11 of 20 | ENST00000397752.8 | NP_000236.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00132 AC: 192AN: 145050Hom.: 1 Cov.: 31
GnomAD4 exome AF: 0.00105 AC: 1531AN: 1455696Hom.: 3 Cov.: 35 AF XY: 0.00105 AC XY: 757AN XY: 724364
GnomAD4 genome AF: 0.00132 AC: 192AN: 145166Hom.: 1 Cov.: 31 AF XY: 0.00127 AC XY: 90AN XY: 70714
ClinVar
Submissions by phenotype
not specified Benign:4
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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. -
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. -
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not provided Uncertain:1
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Renal cell carcinoma Benign:1
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Papillary renal cell carcinoma type 1 Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at