rs876657728
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138691.3(TMC1):c.1676G>A(p.Trp559Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
TMC1
NM_138691.3 stop_gained
NM_138691.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 9.75
Genes affected
TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 9-72805491-G-A is Pathogenic according to our data. Variant chr9-72805491-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 228406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72805491-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.1676G>A | p.Trp559Ter | stop_gained | 18/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.1679G>A | p.Trp560Ter | stop_gained | 15/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.1676G>A | p.Trp559Ter | stop_gained | 18/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000396 AC: 6AN: 151538Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251466Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461504Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727076
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 23, 2020 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change creates a premature translational stop signal (p.Trp559*) in the TMC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMC1 are known to be pathogenic (PMID: 11850618, 22105175). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with congenital deafness (PMID: 29196752). ClinVar contains an entry for this variant (Variation ID: 228406). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 22, 2016 | The p.Trp559X variant in TMC1 has now been identified by our laboratory in 2 ind ividuals with hearing loss, and both of them have a second pathogenic variant in TMC1. This variant has not been identified in large population studies. This no nsense variant leads to a premature termination codon at position 559, which is predicted to lead to a truncated or absent protein. Loss of function variants af fecting both copies of TMC1 is an established disease mechanism for nonsyndromic autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner base d upon the predicted impact of the variant. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at