rs201632198
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5
The NM_001256317.3(TMPRSS3):c.325C>T(p.Arg109Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R109Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001256317.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.325C>T | p.Arg109Trp | missense_variant, splice_region_variant | 5/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.325C>T | p.Arg109Trp | missense_variant, splice_region_variant | 5/13 | ||
TMPRSS3 | NM_032405.2 | c.325C>T | p.Arg109Trp | missense_variant, splice_region_variant | 5/9 | ||
TMPRSS3 | NM_032404.3 | c.-57C>T | splice_region_variant, 5_prime_UTR_variant | 2/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.325C>T | p.Arg109Trp | missense_variant, splice_region_variant | 5/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251350Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135878
GnomAD4 exome AF: 0.000106 AC: 155AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83AN XY: 727242
GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 05, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2023 | Identified with a second variant in additional patients with sensorineural hearing loss in published literature (Lechowicz et al., 2017); Published functional studies demonstrate a damaging effect due to failure to undergo proteolytic cleavage and activate the epithelial sodium channel (Guipponi et al., 2002; Lee et al., 2003; Andreasen et al., 2006); 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: 12393794, 28246597, 12920079, 11424922, 16524950, 29937438, 28566687, 18928407, 29072634, 24526180, 31589614, 32860223, 34426522, 34868270, 36871673, 23958653, 35961784) - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 03, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the TMPRSS3 protein (p.Arg109Trp). This variant is present in population databases (rs201632198, gnomAD 0.2%). This missense change has been observed in individual(s) with deafness (PMID: 11424922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 46114). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). This variant disrupts the p.Arg109 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24853665; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The TMPRSS3 c.325C>T (p.Arg109Trp) variant has been reported in one consanguineous family with autosomal recessive hearing loss, and the variant segregated with disease in three affected homozygote individuals and 5 heterozygous obligate carriers (Ben-Yosef et al. 2001). The p.Arg109Trp variant was absent from 318 controls and is reported at a frequency of 0.00016 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes and yeast demonstrated that the p.Arg109Trp variant leads to a protein product that fails to undergo proteolytic cleavage and is therefore only partially active (Guipponi et al. 2002; Lee et al. 2003; Andreasen et al. 2006). Based on the evidence, the p.Arg109Trp variant is classified as a likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12393794, 23958653). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046114 / PMID: 11424922). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11424922, 28566687). A different missense change at the same codon (p.Arg109Gln) has been reported to be associated with TMPRSS3 related disorder (PMID: 24853665). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2013 | The Arg109Trp variant in TMPRSS3 has been reported in one family with hearing lo ss in which the variant segregated with disease (homozygous) in 3 affected and w as heterozygous in 5 unaffected family members, and was absent from 159 controls (318 chromosomes) (Ben-Yosef 2001). Our laboratory has also identified this var iant as a compound heterozygote with other pathogenic mutations in two probands with hearing loss. And finally, two studies have reported that the Arg109Trp var iant leads to a protein product that is only partially active (Guipponi 2002, An dreasen 2006). In summary, this variant meets our criteria to be classified as p athogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at