rs28939084
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001256317.3(TMPRSS3):c.1208C>T(p.Pro403Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,322 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 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
TMPRSS3
NM_001256317.3 missense
NM_001256317.3 missense
Scores
9
3
1
Clinical Significance
Conservation
PhyloP100: 9.17
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 16 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001256317.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
?
Variant 21-42375852-G-A is Pathogenic according to our data. Variant chr21-42375852-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42375852-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.1208C>T | p.Pro403Leu | missense_variant | 12/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.1211C>T | p.Pro404Leu | missense_variant | 12/13 | ||
TMPRSS3 | NM_032404.3 | c.830C>T | p.Pro277Leu | missense_variant | 9/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.1208C>T | p.Pro403Leu | missense_variant | 12/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151794Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251368Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461528Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727044
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 404 of the TMPRSS3 protein (p.Pro404Leu). This variant is present in population databases (rs28939084, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 11462234, 31850270). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4945). 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%. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). For these reasons, this variant has been classified as Pathogenic. - |
Ear malformation Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
Polyphen
D;D;D;D
Vest4
0.94, 0.94
MutPred
0.97
.;Gain of catalytic residue at P404 (P = 0.007);Gain of catalytic residue at P404 (P = 0.007);.;
MVP
0.98
MPC
0.53
ClinPred
D
GERP RS
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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