21-42376552-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_001256317.3(TMPRSS3):āc.1180G>Cā(p.Asp394His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,058 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D394N) has been classified as Uncertain significance.
Frequency
Consequence
NM_001256317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.1180G>C | p.Asp394His | missense_variant | 11/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.1183G>C | p.Asp395His | missense_variant | 11/13 | ||
TMPRSS3 | NM_032404.3 | c.802G>C | p.Asp268His | missense_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.1180G>C | p.Asp394His | missense_variant | 11/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250594Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135624
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461058Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726836
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 46099). This missense change has been observed in individual(s) with deafness (PMID: 34868270). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs111033537, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 395 of the TMPRSS3 protein (p.Asp395His). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 17, 2010 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at