rs727503493

Positions:

chr21-42389042-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001256317.3(TMPRSS3):c.208delC(p.His70fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 1 hom. )

Consequence

TMPRSS3
NM_001256317.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 3.49

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:

TMPRSS3 (HGNC:):

TMPRSS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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;

PP5

Variant 21-42389042-TG-T is Pathogenic according to our data. Variant chr21-42389042-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 165492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42389042-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.208delC	p.His70fs	frameshift_variant, splice_region_variant	4/13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 linkuse as main transcript	c.208delC	p.His70fs	frameshift_variant, splice_region_variant	4/13		NP_076927.1	P57727-1
TMPRSS3	NM_032405.2 linkuse as main transcript	c.208delC	p.His70fs	frameshift_variant, splice_region_variant	4/9		NP_115781.1	P57727-3
TMPRSS3	NM_032404.3 linkuse as main transcript	c.-174delC		5_prime_UTR_variant	1/10		NP_115780.1	P57727-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 linkuse as main transcript	c.208delC	p.His70fs	frameshift_variant, splice_region_variant	4/13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000490

AC:

123

AN:

251230

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000933

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000844

AC:

1234

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000789

AC XY:

574

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000727

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000532

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000909

Hom.:

Bravo

AF:

0.000536

EpiCase

AF:

0.000872

EpiControl

AF:

0.000771

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8

Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	TMPRSS3 c.208delC (p.H70Tfs) is a frameshift variant that is predicted to result in a nonfunctional protein. This variant has been reported previously in the homozygous or compound heterozygous state in multiple individuals with autosomal recessive nonsyndromic hearing loss (PMID: 11907649, 21534946, 21786053; 26036852). -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 26, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TMPRSS3 c.208delC (p.His70ThrfsTer19) variant has been reported in at least six studies and is found in a total of at least 27 individuals with nonsyndromic hearing loss, including 24 in a homozygous state and three in a compound heterozygous state (Wattenhofer et al. 2002; Ahmed et al. 2004; Kecmanovic et al. 2009; Weegerink et al. 2011; Lee et al. 2012; Battelino et al. 2015). The variant segregated with disease in at least three unrelated families. The p.His70ThrfsTer19 variant was absent from 700 control alleles but is reported at a frequency of 0.00074 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.His70ThrfsTer19 variant results in a frameshift, and is predicted to result in premature termination of the protein. Due to the potential impact of frameshift variants and the supporting evidence from the literature, the p.His70ThrfsTer19 variant is classified as 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	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 20, 2024	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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (136 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 15447792, 27573290, 19170735, 21534946, 11907649, 21786053, 26036852, 28566687, 29293505, 31270413, 31980526, 31412945, 34171171, 31589614, 32853555, 32860223) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 03, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.His70Thrfs*19) in the TMPRSS3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMPRSS3 are known to be pathogenic (PMID: 16021470, 26969326). This variant is present in population databases (rs727503493, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 11907649, 28566687, 29293505). This variant is also known as 207delC. ClinVar contains an entry for this variant (Variation ID: 165492). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Feb 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TMPRSS3: PM3:Very Strong, PVS1, PP1:Strong, PM2 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.208delC (p.H70Tfs*19) alteration, located in exon 4 (coding exon 3) of the TMPRSS3 gene, consists of a deletion of one nucleotide at position 208, causing a translational frameshift with a predicted alternate stop codon after 19 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.048% (136/282628) total alleles studied. The highest observed frequency was 0.097% (10/10364) of Ashkenazi Jewish alleles. This alteration has been reported homozygous or compound heterozygous with a second TMPRSS3 alteration in multiple patients with features consistent with TMPRSS3-related deafness (Wattenhofer, 2002; Battelino, 2016; Lechowicz, 2017; Likar, 2018; Roman, 2020; Moon, 2021). Based on the available evidence, this alteration is classified as pathogenic. -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jan 05, 2024

This sequence change in TMPRSS3 is a frameshift variant predicted to cause a premature stop codon, p.(His70Thrfs*19), in biologically relevant exon 4/13 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.1% (1,202/1,180,022 alleles) in the European (non-Finnish) population. The variant has been reported to segregate with hearing loss in affected family members from two unrelated families (PMID: 21534946, 26036852). This variant has been detected in multiple individuals with hearing loss. Of those individuals, at least two individuals were homozygous while the majority of the reported individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 29293505, 30242206, 26036852, 28566687). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PVS1 -

Hearing impairment

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PVS1_Strong, PM2_Supporting, PM5_Moderate -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 08, 2024

The p.His70ThrfsX19 variant in TMPRSS3 has been reported in the homozygous or compound heterozygous state in more than 10 individuals with nonsyndromic hearing loss and segregated with disease in more than 10 affected relatives from over 5 families (Wattenhofer 2002 PMID: 11907649, Ahmed 2004 PMID: 15447792, Kecmanović 2008 PMID: 19170735, Weegerink 2011 PMID: 21786053, Lee 2012 PMID: 21534946, Battelino 2016 PMID: 26036852, LMM data). It has been identified in 0.1% (1202/1180022) of European chromosomes, including 1 homozygote by gnomAD (http://gnomAD.broadinstitute.org, v4.0.0); however, this frequency is low enough to be consistent with a recessive carrier frequency for hearing loss. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 70 and leads to a premature stop codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the TMPRSS3 gene is an established disease mechanism in autosomal recessive nonsyndromic hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting. -

TMPRSS3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The TMPRSS3 c.208delC variant is predicted to result in a frameshift and premature protein termination (p.His70Thrfs*19). This variant has been reported to be causative for autosomal recessive nonsyndromic hearing loss (Wattenhofer et al. 2002. PubMed ID: 11907649; Battelino et al. 2016. PubMed ID: 26036852; Lechowicz et al. 2017. PubMed ID: 28566687). This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in TMPRSS3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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