rs397517376
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001256317.3(TMPRSS3):c.579_580insA(p.Cys194MetfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
TMPRSS3
NM_001256317.3 frameshift
NM_001256317.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.60
Genes affected
TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 21-42384006-A-AT is Pathogenic according to our data. Variant chr21-42384006-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 517148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.579_580insA | p.Cys194MetfsTer17 | frameshift_variant | 7/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.579_580insA | p.Cys194MetfsTer17 | frameshift_variant | 7/13 | ||
TMPRSS3 | NM_032404.3 | c.198_199insA | p.Cys67MetfsTer17 | frameshift_variant | 4/10 | ||
TMPRSS3 | NM_032405.2 | c.579_580insA | p.Cys194MetfsTer17 | frameshift_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.579_580insA | p.Cys194MetfsTer17 | frameshift_variant | 7/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251208Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135786
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461762Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727172
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74344
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | TMPRSS3: PVS1, PM3:Strong, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Cys194Metfs*17) in the TMPRSS3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMPRSS3 are known to be pathogenic (PMID: 16021470, 26969326). This variant is present in population databases (rs397517376, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with autosomal recessive non-syndromic hearing loss (PMID: 26036852, 28566687, 30622556). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 517148). For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Dec 08, 2023 | - - |
Hearing impairment Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PVS1_Strong, PM2_Moderate - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 02, 2020 | The p.Cys194MetfsX17 variant in TMPRSS3 has been reported in at least 6 individuals with hearing loss who were compound heterozygous for a second TMPRSS3 pathogenic variant (Battelino 2016 PMID 26036852, Lechowicz 2017 PMID 28566687, Lechowicz 2016 PMID 26408194, Morgan 2018 PMID 30622556). It has also been identified in 0.007% (9/113638) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 194 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TMPRSS3 gene is an established disease mechanism in autosomal recessive hearing loss.In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2, PM3_VeryStrong. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at