rs45598239
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001256317.3(TMPRSS3):c.268G>A(p.Ala90Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0447 in 1,614,130 control chromosomes in the GnomAD database, including 1,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.032 ( 124 hom., cov: 33)
Exomes 𝑓: 0.046 ( 1793 hom. )
Consequence
TMPRSS3
NM_001256317.3 missense
NM_001256317.3 missense
Scores
8
5
Clinical Significance
Conservation
PhyloP100: 4.28
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0037552118).
BP6
?
Variant 21-42388983-C-T is Benign according to our data. Variant chr21-42388983-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42388983-C-T is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPRSS3 | NM_001256317.3 | c.268G>A | p.Ala90Thr | missense_variant | 4/13 | ENST00000644384.2 | |
TMPRSS3 | NM_024022.4 | c.268G>A | p.Ala90Thr | missense_variant | 4/13 | ||
TMPRSS3 | NM_032405.2 | c.268G>A | p.Ala90Thr | missense_variant | 4/9 | ||
TMPRSS3 | NM_032404.3 | c.-114G>A | 5_prime_UTR_variant | 1/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPRSS3 | ENST00000644384.2 | c.268G>A | p.Ala90Thr | missense_variant | 4/13 | NM_001256317.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0325 AC: 4946AN: 152208Hom.: 124 Cov.: 33
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GnomAD3 exomes AF: 0.0318 AC: 7990AN: 251426Hom.: 207 AF XY: 0.0320 AC XY: 4353AN XY: 135894
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GnomAD4 exome AF: 0.0459 AC: 67147AN: 1461804Hom.: 1793 Cov.: 33 AF XY: 0.0447 AC XY: 32521AN XY: 727196
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GnomAD4 genome ? AF: 0.0325 AC: 4945AN: 152326Hom.: 124 Cov.: 33 AF XY: 0.0306 AC XY: 2283AN XY: 74488
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TwinsUK
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192
ALSPAC
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199
ESP6500AA
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40
ESP6500EA
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415
ExAC
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4003
Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 26, 2010 | Ala90Thr in exon 4 of TMPRSS3: This variant has been identified in 4/178 (2.2%) probands with hearing loss (Rehm, unpublished data; Hutchin 2005) and was absent from 165 controls. However, in all 4 probands, a second variant was not identif ied. In addition, this variant has been identified in several control studies (r s45598239 ? 4 submissions) including 2/10 controls in our laboratory. In summary , this data suggests that the variant is benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 16, 2014 | - - |
Autosomal recessive nonsyndromic hearing loss 8 Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 20, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;D;.;D
Vest4
0.24, 0.21, 0.50
MPC
0.48
ClinPred
T
GERP RS
Varity_R
gMVP
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