chr21-42376612-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_001256317.3(TMPRSS3):c.1120G>A(p.Val374Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001256317.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.1120G>A | p.Val374Met | missense_variant | Exon 11 of 13 | ENST00000644384.2 | NP_001243246.1 | |
TMPRSS3 | NM_024022.4 | c.1123G>A | p.Val375Met | missense_variant | Exon 11 of 13 | NP_076927.1 | ||
TMPRSS3 | NM_032404.3 | c.742G>A | p.Val248Met | missense_variant | Exon 8 of 10 | NP_115780.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251414Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135882
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461756Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727176
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
not specified Uncertain:1
The p.Val375Met variant in TMPRSS3 has not been previously reported in individua ls with hearing loss, but has been identified in 3/111694 European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbS NP rs775508015). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational pr ediction tools and conservation analyses do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of the p.V al375Met variant is uncertain. -
Inborn genetic diseases Uncertain:1
The c.1123G>A (p.V375M) alteration is located in exon 11 (coding exon 10) of the TMPRSS3 gene. This alteration results from a G to A substitution at nucleotide position 1123, causing the valine (V) at amino acid position 375 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at