21-42388436-G-T

Variant names:

• chr21-42388436-G-T
• rs147231991
• NM_001256317.3:c.413C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 11P and 2B. PM1 PP2 PP5_Very_Strong BP4 BS1_Supporting

The NM_001256317.3(TMPRSS3):​c.413C>A​(p.Ala138Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00195 in 1,614,240 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A138T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 5.34
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001256317.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.
• PP5: Variant 21-42388436-G-T is Pathogenic according to our data. Variant chr21-42388436-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 46119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09016231). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00203 (2964/1461892) while in subpopulation NFE AF = 0.00252 (2799/1112012). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAdExome4. There are 1397 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.413C>A	p.Ala138Glu	missense_variant	Exon 5 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.413C>A	p.Ala138Glu	missense_variant	Exon 5 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.413C>A	p.Ala138Glu	missense_variant	Exon 5 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.32C>A	p.Ala11Glu	missense_variant	Exon 2 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.413C>A	p.Ala138Glu	missense_variant	Exon 5 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000919 AC: 231 AN: 251450 AF XY: 0.000912

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00203 AC: 2964 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.00192 AC XY: 1397 AN XY: 727246

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00252 AC: 2799 AN: 1112012

Other (OTH) AF: 0.00137 AC: 83 AN: 60396

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74500

African (AFR) AF: 0.000337 AC: 14 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00153 Hom.: 2

Bravo AF: 0.00100

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000799 AC: 97

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:14

Jan 27, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c. 413C>A (p. Ala138Glu) missense variant in the TMPRSS3 gene has previously been reported as homozygous in two siblings who were affected with autosomal recessive non-syndromic hearing loss [Hutchin T et al., (2005)]. Additionally, this variant has been seen in trans with a known pathogenic variant (Ala306Thr) and also co-segregated with disease in multiple affected family members in several families [Weegerink NJ et al., (2011)]. The prevalence of this variant in affected individuals is significantly increased compared with the prevalence in controls. The frequency of this variant in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC) is lower than the disease-allele frequency, and no homozygotes for this variant are observed in the population databases. Several computational algorithms predict a deleterious effect of this variant on the protein. Finally, reputable clinical sources have classified this variant as either Likely Pathogenic or Pathogenic. Therefore, this collective evidence supports the Likely Pathogenic classification of the c.413C>A (p. Ala138Glu) variant in the TMPRSS3 gene for Non-syndromic hearing loss (DFNB8/10). We have confirmed this finding in our laboratory using Sanger sequencing. -

Aug 31, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 04, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2018

Genetics Laboratory, Department of Biology, Semnan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

The identified mutation leads to the substitution of Alanine 138 to Glutamic acid (A138E) in the TMPRSS3 protein. Hence, this substitution alters the amino acid sequence and leads to abnormal protein function. -

Sep 29, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

in compound heterozygosis with the c.346G>A variant in a subject with non-syndromic sensorineural postlingual progressive hearing loss (sporadic) -

Apr 07, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TMPRSS3 c.413C>A (p.Ala138Glu) results in a non-conservative amino acid change located in the SRCR domain (IPR001190) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 251450 control chromosomes. c.413C>A has been reported in the literature in multiple individuals affected with Deafness, autosomal recessive 8 (examples- Hutchin_2005, Weegerink_2011, Eppsteiner_2012), and has been shown to segregate with disease in affected family members. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (277 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (highest allele count: p.(Ala138Thr) - v2: 165 heterozygotes, 0 homozygotes; v3: 78 heterozygotes, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (I) 0600 - Variant is located in the annotated scavenger receptor cysteine-rich domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple unrelated individuals with hearing loss (PMID: 16283880, 21786053, 22975204, 30242206), and as pathogenic in ClinVar and the Deafness Variation Database. (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated with disease in at least two families with autosomal recessive non-syndromic hearing impairment (PMID: 21786053). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Dec 01, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TMPRSS3 c.413C>A (p.Ala138Glu) variant was identified in a total of 14 individuals with an autosomal recessive form of hearing loss, including in two homozygotes from one family and in a total of 12 compound heterozygotes from seven unrelated families. The variant was also found in a heterozygous state in three unaffected parents (Hutchin et al. 2005; Weegerink et al. 2011; Eppsteiner et al. 2012). The p.Ala138Glu variant was absent from 165 controls, but is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala138Glu 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. -

Nov 10, 2022

The Shared Resource Centre "Genome", Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:10

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMPRSS3: PM3:Very Strong, PP1:Strong, PM2:Supporting, BP4 -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 25262649, 31152317, 16283880, 22975204, 28566687, 29431110, 31053783, 28695016, 31589614, 36147510, 34868270, 34599368, 34758253, 31980526, 35580552, 35052694, 21786053, 36515421, 36555390, 37713394, 38374194, 37811145, 38593426, 38523675, 38691166, Ajam-Hosseini[Preprint], Abhinay2024[CaseReport]) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 31, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM3_very_strong -

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 138 of the TMPRSS3 protein (p.Ala138Glu). This variant is present in population databases (rs147231991, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with deafness (PMID: 16283880, 21786053, 22975204, 28566687, 29431110, 30242206, 31152317). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.A11E . ClinVar contains an entry for this variant (Variation ID: 46119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMPRSS3 protein function. For these reasons, this variant has been classified as Pathogenic. -

Nonsyndromic genetic hearing loss Pathogenic:1

Jan 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in TMPRSS3 is predicted to replace alanine with glutamic acid at codon 138, p.(Ala138Glu). The alanine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the scavenger receptor cysteine-rich (SRCR) domain. There is a large physicochemical difference between alanine and glutamic acid. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.2% (2,942/1,180,048 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: 21786053). 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: 37811145, 37713394, 30242206, 22975204, 21786053). Computational evidence is uninformative for the missense substitution (REVEL = 0.595). 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 -

Hearing impairment Pathogenic:1

Apr 12, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1_Strong, PM2_Moderate, PP3_Supporting -

Rare genetic deafness Pathogenic:1

Mar 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala138Glu variant in TMPRSS3 has been reported in the homozygous or compou nd heterozygous state in more than 10 probands with nonsyndromic hearing loss an d has segregated in 5 affected family members (Eppsteiner 2012, Hutchin 2005, We egerink 2011, LMM data). This variant has been identified in 0.1% (82/67696) Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; rs147231991); however, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein. In summary, the p.Ala138Glu variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the previous reports of biallelic states in affected individuals and segregations with hearing loss. ACMG/AMP Crit eria applied: PM3_VeryStrong, PP1_Strong, PP3. -

TMPRSS3-related disorder Pathogenic:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TMPRSS3 c.413C>A variant is predicted to result in the amino acid substitution p.Ala138Glu. This variant has been reported to be causative for autosomal recessive nonsyndromic hearing loss (Hutchin et al. 2005. PubMed ID: 16283880; Lechowicz et al. 2017. PubMed ID: 28566687; Weegerink et al. 2011. PubMed ID: 21786053; Eppsteiner et al. 2012. PubMed ID: 22975204). This variant is reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T;T;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T;.;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.090	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M
PhyloP100		5.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	.;N;N;N;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	.;D;D;D;D
Sift4G	Uncertain	0.0040	.;D;D;D;D
Polyphen		0.89	P;D;D;.;D
Vest4		0.62, 0.62, 0.62
MVP		0.91
MPC		0.49
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.77
gMVP		0.89
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs147231991; hg19: chr21-43808545;