9-72694578-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138691.3(TMC1):c.100C>T(p.Arg34Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,612,698 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
Consequence
NM_138691.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC1 | NM_138691.3 | c.100C>T | p.Arg34Ter | stop_gained | 7/24 | ENST00000297784.10 | |
TMC1 | XM_017014256.2 | c.103C>T | p.Arg35Ter | stop_gained | 4/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC1 | ENST00000297784.10 | c.100C>T | p.Arg34Ter | stop_gained | 7/24 | 1 | NM_138691.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151928Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000561 AC: 14AN: 249642Hom.: 0 AF XY: 0.0000519 AC XY: 7AN XY: 134954
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1460652Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 726594
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152046Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74296
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 7 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004103, PMID:11850618, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000056, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Oct 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Aug 01, 2020 | TMC1 c.100C>T, p.R34* is homozygous in 3 Palestinian children with profound pre-lingual hearing loss It was found also in 2 Palestinian children with hearing loss in compound heterozygosity with TMC1 c.1532C>A. The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Pathogenic, no assertion criteria provided | research | Hereditary Research Laboratory, Bethlehem University | Jun 04, 2016 | FA3 moderate HL at 6y; FA4 profound at 18m - |
Pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 07, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 17877751, 27766948, 24949729, 11850618, 29048421, 20373850, 19187973, 31854501, 31541171, 34426522, 32802042, 32747562, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 18, 2017 | The p.Arg34Ter variant is the most frequently reported pathogenic variant of TMC1 and is likely a founder variant in North African and Middle Eastern populations (Kurima 2002, Ben Said 2010, Shafique 2014, and Dallol 2016). The c.100C>T variant creates a premature termination codon in exon 7 and is predicted to result in a truncated or absent protein product. Based on these observations the p.Arg34Ter variant has been classified pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg34*) 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 (rs121908073, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 11850618, 17877751, 31854501). ClinVar contains an entry for this variant (Variation ID: 4103). For these reasons, this variant has been classified as Pathogenic. - |
Autosomal dominant nonsyndromic hearing loss 36 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Hearing loss, autosomal recessive Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 13, 2012 | The p.Arg34X variant in TMC1 has been reported in more than 23 probands with sen sorineural hearing loss (Kurima 2002, Ben Said 2010, Sirmaci 2009, Kitajiri 2007 , Shafique 2014). Most of these probands, as well as their affected relatives, w ere homozygous for the variant. The p.Arg34X variant has also been identified in 4/15682 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs121908073). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Animal models in mice have shown that loss of TM C1 function causes an auditory phenotype (Kurima 2002). This nonsense variant le ads to a premature termination codon at position 34, which is predicted to lead to a truncated or absent protein. In summary, the p.Arg34X variant meets our cri teria to be classified as pathogenic for hearing loss in an autosomal recessive manner. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at