21-42383062-C-G
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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):āc.753G>Cā(p.Trp251Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,804 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 Pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
TMPRSS3
NM_001256317.3 missense
NM_001256317.3 missense
Scores
8
5
1
Clinical Significance
Conservation
PhyloP100: 5.38
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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001256317.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 21-42383062-C-G is Pathogenic according to our data. Variant chr21-42383062-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42383062-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.753G>C | p.Trp251Cys | missense_variant | 8/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.753G>C | p.Trp251Cys | missense_variant | 8/13 | ||
TMPRSS3 | NM_032405.2 | c.753G>C | p.Trp251Cys | missense_variant | 8/9 | ||
TMPRSS3 | NM_032404.3 | c.372G>C | p.Trp124Cys | missense_variant | 5/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.753G>C | p.Trp251Cys | missense_variant | 8/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461804Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727210
GnomAD4 exome
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1
AN:
1461804
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32
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1
AN XY:
727210
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: 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 | Aug 01, 2001 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | TMPRSS3: PP1:Strong, PM1, PM2, PM3, PS3:Supporting - |
Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Otolaryngology ā Head & Neck Surgery, Cochlear Implant Center | Apr 12, 2021 | PS1_Strong, PM2_Moderate, PM5_Moderate, PP3_Supporting - |
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
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;.;M
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
Polyphen
D;D;D;.;D
Vest4
0.95, 0.95, 0.87
MutPred
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP
0.95
MPC
0.67
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -29
Find out detailed SpliceAI scores and Pangolin per-transcript scores at