rs200841002
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_138691.3(TMC1):c.472C>T(p.Arg158Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,864 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158H) has been classified as Uncertain significance.
Frequency
Consequence
NM_138691.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.472C>T | p.Arg158Cys | missense_variant | 10/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.475C>T | p.Arg159Cys | missense_variant | 7/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.472C>T | p.Arg158Cys | missense_variant | 10/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251300Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135830
GnomAD4 exome AF: 0.000203 AC: 297AN: 1461726Hom.: 0 Cov.: 31 AF XY: 0.000199 AC XY: 145AN XY: 727156
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2016 | The p.Arg158Cys variant in TMC1 has been identified by our laboratory in the het erozygous state in 2 individuals with hearing loss; however, one of these indivi duals had an alternate genetic cause for the hearing loss. This variant has also been identified in 19/126642 European chromosomes by the Genome Aggregation Dat abase (gnomAD, http://gnomAD.broadinstitute.org; dbSNP rs200841002). Although th is variant has been seen in the general population, its frequency is not high en ough to rule out a pathogenic role. Computational prediction tools and conservat ion analyses suggest that this variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. In summary, the clin ical significance of the p.Arg158Cys variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 13, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at