rs201632198

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_032404.3(TMPRSS3):c.-57C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TMPRSS3
NM_032404.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 2.77

Variant links:

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]

TMPRSS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-42388524-G-A is Pathogenic according to our data. Variant chr21-42388524-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 46114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42388524-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.325C>T	p.Arg109Trp	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000644384.2	NP_001243246.1	P57727-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.325C>T	p.Arg109Trp	missense_variant, splice_region_variant	Exon 5 of 13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251350

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

155

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00226

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000746

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000281

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 03, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2024	Identified with a second variant in additional patients with sensorineural hearing loss in published literature (PMID: 28566687); Published functional studies demonstrate a damaging effect due to failure to undergo proteolytic cleavage and activate the epithelial sodium channel (PMID: 12920079, 16524950, 12393794); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12393794, 28246597, 16524950, 29937438, 18928407, 29072634, 24526180, 31589614, 32860223, 34426522, 34868270, 36871673, 23958653, 35961784, 37331337, 11424922, 12920079, 28566687) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the TMPRSS3 protein (p.Arg109Trp). This variant is present in population databases (rs201632198, gnomAD 0.2%). This missense change has been observed in individual(s) with deafness (PMID: 11424922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 46114). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). This variant disrupts the p.Arg109 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24853665; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 8

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 8/10 (MIM#601072). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 47 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 42 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been detected in multiple families with hearing loss (PMID: 34868270) and regarded as pathogenic by diagnostic laboratories in ClinVar. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). The parents of this proband have been tested by an external laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, flagged submission	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TMPRSS3 c.325C>T (p.Arg109Trp) variant has been reported in one consanguineous family with autosomal recessive hearing loss, and the variant segregated with disease in three affected homozygote individuals and 5 heterozygous obligate carriers (Ben-Yosef et al. 2001). The p.Arg109Trp variant was absent from 318 controls and is reported at a frequency of 0.00016 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in Xenopus oocytes and yeast demonstrated that the p.Arg109Trp variant leads to a protein product that fails to undergo proteolytic cleavage and is therefore only partially active (Guipponi et al. 2002; Lee et al. 2003; Andreasen et al. 2006). Based on the evidence, the p.Arg109Trp variant is classified as a likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Jun 10, 2024	Pathogenic by Deafness Variation Datatbase -
Pathogenic, criteria provided, single submitter	clinical testing	3billion, Medical Genetics	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12393794, 23958653). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.47). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046114 / PMID: 11424922). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 11424922, 28566687). A different missense change at the same codon (p.Arg109Gln) has been reported to be associated with TMPRSS3 related disorder (PMID: 24853665). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 01, 2013

The Arg109Trp variant in TMPRSS3 has been reported in one family with hearing lo ss in which the variant segregated with disease (homozygous) in 3 affected and w as heterozygous in 5 unaffected family members, and was absent from 159 controls (318 chromosomes) (Ben-Yosef 2001). Our laboratory has also identified this var iant as a compound heterozygote with other pathogenic mutations in two probands with hearing loss. And finally, two studies have reported that the Arg109Trp var iant leads to a protein product that is only partially active (Guipponi 2002, An dreasen 2006). In summary, this variant meets our criteria to be classified as p athogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

.;D;D;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.70

D;D;D;D;D

MetaSVM

Uncertain

0.065

MutationAssessor

Pathogenic

3.0

M;M;M;.;M

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.2

.;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0

.;D;D;D;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.96, 0.95, 0.96, 0.87

MVP

0.90

MPC

0.53

ClinPred

0.88

GERP RS

4.0

Varity_R

0.88

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over