rs727504304
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate
The NM_001256317.3(TMPRSS3):c.1189C>T(p.Gln397Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
TMPRSS3
NM_001256317.3 stop_gained, splice_region
NM_001256317.3 stop_gained, splice_region
Scores
4
1
2
Splicing: ADA: 0.9942
2
Clinical Significance
Conservation
PhyloP100: 6.98
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.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
PP5
?
Variant 21-42376543-G-A is Pathogenic according to our data. Variant chr21-42376543-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 177740.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42376543-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.1189C>T | p.Gln397Ter | stop_gained, splice_region_variant | 11/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.1192C>T | p.Gln398Ter | stop_gained, splice_region_variant | 11/13 | ||
TMPRSS3 | NM_032404.3 | c.811C>T | p.Gln271Ter | stop_gained, splice_region_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.1189C>T | p.Gln397Ter | stop_gained, splice_region_variant | 11/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2013 | The Gln398X variant in TMPRSS3 has been previously reported in 1 homozygous indi vidual with SNHL, was found to segregate with disease in 2 affected homozygous r elatives, and has not been identified in large population studies. This nonsense variant leads to a premature termination codon at position 398, which is predic ted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A
Vest4
0.91, 0.84
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at