chr21-42388935-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_001256317.3(TMPRSS3):c.316C>T(p.Arg106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,613,668 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106H) has been classified as Uncertain significance.
Frequency
Consequence
NM_001256317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.316C>T | p.Arg106Cys | missense_variant | 4/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.316C>T | p.Arg106Cys | missense_variant | 4/13 | ||
TMPRSS3 | NM_032405.2 | c.316C>T | p.Arg106Cys | missense_variant | 4/9 | ||
TMPRSS3 | NM_032404.3 | c.-66C>T | 5_prime_UTR_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.316C>T | p.Arg106Cys | missense_variant | 4/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000215 AC: 54AN: 251448Hom.: 1 AF XY: 0.000280 AC XY: 38AN XY: 135910
GnomAD4 exome AF: 0.000380 AC: 555AN: 1461366Hom.: 1 Cov.: 32 AF XY: 0.000374 AC XY: 272AN XY: 727028
GnomAD4 genome AF: 0.000105 AC: 16AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74472
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 13, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 106 of the TMPRSS3 protein (p.Arg106Cys). This variant is present in population databases (rs139805921, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with deafness (PMID: 23967202, 28246597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381714). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMPRSS3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 29, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27627659, 23967202, 28695016, 28246597, 34426522, 31589614, 34795337, 34868270, 36147510, 37331337) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | TMPRSS3: PM3:Very Strong, PM2 - |
Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2020 | Variant summary: TMPRSS3 c.316C>T (p.Arg106Cys) results in a non-conservative amino acid change located in the scavenger receptor cysteine-rich (SRCR) domain (IPR001190); most SRCR domains have six to eight cysteines that participate in intradomain disulfide bonds (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251448 control chromosomes in the gnomAD database, including 1 homozygote. The variant, c.316C>T, has been reported in the literature in individuals affected with late onset hearing loss (Gao_2017, Miyagawa_2013), including a large Chinese family, where the variant in combination with a presumed severe mutation in trans (c.916G>A (p.Ala306Thr)) resulted in a milder phenotype (Gao_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (n=1) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Supporting, PP3_Supporting - |
TMPRSS3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 17, 2023 | The TMPRSS3 c.316C>T variant is predicted to result in the amino acid substitution p.Arg106Cys. This variant has been reported in individuals with late-onset hearing loss (Supplemental Table 2, Miyagawa et al. 2013. PubMed ID: 23967202). This variant has also been reported in the compound heterozygous state in individuals with post lingual, milder hearing impairments (Patients II:2, II:3, and II:5, Gao et al. 2017. PubMed ID: 28246597) and in the homozygous state in an individual with perilingual hearing loss (Pavlenkova et al. 2021. PubMed ID: 34795337). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/21-43809044-G-A). This variant is predicted to lead to a mild form of hearing loss and structural protein modeling suggesting that a homozygous p.Arg106Cys variant would lead to a subtle protein change or would be similar to that of wildtype protein (Gao et al. 2017. PubMed ID: 28246597). This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/381714/). Taken together, we interpret this variant as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at