rs181949335
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_001256317.3(TMPRSS3):c.916G>A(p.Ala306Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,614,172 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
TMPRSS3
NM_001256317.3 missense
NM_001256317.3 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 6.91
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 13 ACMG points.
PM1
In a disulfide_bond (size 117) in uniprot entity TMPS3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001256317.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.802
PP5
Variant 21-42382101-C-T is Pathogenic according to our data. Variant chr21-42382101-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 46131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42382101-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-42382101-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.916G>A | p.Ala306Thr | missense_variant | 9/13 | ENST00000644384.2 | NP_001243246.1 | |
TMPRSS3 | NM_024022.4 | c.916G>A | p.Ala306Thr | missense_variant | 9/13 | NP_076927.1 | ||
TMPRSS3 | NM_032405.2 | c.916G>A | p.Ala306Thr | missense_variant | 9/9 | NP_115781.1 | ||
TMPRSS3 | NM_032404.3 | c.535G>A | p.Ala179Thr | missense_variant | 6/10 | NP_115780.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.916G>A | p.Ala306Thr | missense_variant | 9/13 | NM_001256317.3 | ENSP00000494414.1 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152170Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000145 AC: 36AN: 249060Hom.: 0 AF XY: 0.000104 AC XY: 14AN XY: 134822
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GnomAD4 exome AF: 0.000210 AC: 307AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 153AN XY: 727244
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GnomAD4 genome AF: 0.000190 AC: 29AN: 152288Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74456
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Feb 10, 2021 | This variant was identified in compound heterozygosity with another variant in the same gene in a male patient with prelingual bilateral severe hearing loss - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046131). 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: 23958653 , 24526180). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 06, 2018 | Across a selection of the available literature, the TMPRSS3 c.916G>A (p.Ala306Thr) variant has been identified in a homozygous state in two siblings and in a compound heterozygous state in 15 individuals from nine families with autosomal recessive hearing loss (Elbracht et al. 2007; Weegerink et al. 2011; Lee et al. 2013; Chung et al. 2014; Gao et al. 2017). The variant was also found in a heterozygous state in at least three family members with normal hearing. Co-segregation of the variant with disease was demonstrated in at least one family (Gao et al. 2017), and has been suggested to be a founder variant in the Korean population, as two families with the variant were found to share the same haplotype (Chung et al. 2014). The p.Ala306Thr variant was absent from 1770 control chromosomes and is reported at a frequency of 0.00104 in the East Asian population of the Exome Aggregation Consortium. An in vitro yeast-based protease assay showed that the p.Ala306Thr variant-containing protein exhibited significantly reduced protease activity compared to the wild type protein as well as proteins containing other missense variants, consistent with the location of the variant near the Asp304 active site (Chung et al. 2014). Based on the collective evidence, the p.Ala306Thr variant is classified as 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 | research | Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital | - | in compound heterozygosis with the c.1276G>A variant in three siblings with bilateral non-syndromic sensorineural postlingual progressive hearing loss; 7 normal hearing heterozygous of either variant, 2 normal hearing w/o variants (familial) - |
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM3_VeryStrong+PP1+PP3_Moderate+PM2_Supporting - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Prof. Karen Avraham, Tel Aviv University | Jun 10, 2024 | Pathogenic by Deafness Variation Datatbase - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2024 | Published functional studies suggest a significant defect in protease activity compared to wild type (PMID: 24526180); 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: 34416374, 23208854, 21786053, 28246597, 23958653, 17551081, 31045651, 31980526, 31589614, 35961784, 35062939, 34599368, 34868270, 28695016, 34519870, 24526180, 36871673) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 04, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | TMPRSS3: PM3:Very Strong, PP1:Strong, PM2 - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 306 of the TMPRSS3 protein (p.Ala306Thr). This variant is present in population databases (rs181949335, gnomAD 0.06%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 17551081, 23208854, 24526180, 28246597, 28695016, 31045651). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Korean and Chinese ancestry (PMID: 24526180, 28695016). ClinVar contains an entry for this variant (Variation ID: 46131). 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 80%. For these reasons, this variant has been classified as 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_Moderate, PP3_Supporting - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 12, 2019 | The p.Ala306Thr variant in TMPRSS3 has been reported in >10 individuals with autosomal recessive hearing loss and segregated in >10 affected relatives in >5 families (Elbracht 2007, Weegerink 2011, Schrauwen 2012, Lee 2013, Chung 2014, Gao 2017a, Gao 2017b). All affected individuals were either homozygous or compound heterozygous. This variant has also been identified in 0.06% (12/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support an impact on protein function (Chung 2014). Computational prediction tools and conservation analysis also support a functional impact. In summary, the p.Ala306Thr variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.;M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;D;D;D;D
Sift4G
Pathogenic
.;D;D;D;D
Polyphen
D;D;D;D;D
Vest4
0.89, 0.89, 0.88, 0.91
MVP
0.96
MPC
0.52
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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