rs181949335

Variant names:

• chr21-42382101-C-T
• rs181949335
• NM_001256317.3:c.916G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5 PP2 PP3 PP5_Very_Strong

The NM_001256317.3(TMPRSS3):​c.916G>A​(p.Ala306Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,614,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A306V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.91
• Publications: 35 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: Pathogenic. The variant received 12 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-42382100-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2445668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802
• PP5: Variant 21-42382101-C-T is Pathogenic according to our data. Variant chr21-42382101-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 46131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.916G>A	p.Ala306Thr	missense_variant	Exon 9 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.916G>A	p.Ala306Thr	missense_variant	Exon 9 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.916G>A	p.Ala306Thr	missense_variant	Exon 9 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.535G>A	p.Ala179Thr	missense_variant	Exon 6 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.916G>A	p.Ala306Thr	missense_variant	Exon 9 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000145 AC: 36 AN: 249060 AF XY: 0.000104

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000652

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 153 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000250 AC: 278 AN: 1112006

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74456

African (AFR) AF: 0.000169 AC: 7 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000219 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:7

-

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.1276G>A variant in three siblings with bilateral non-syndromic sensorineural postlingual progressive hearing loss; 7 normal hearing heterozygous of either variant, 2 normal hearing w/o variants (familial) -

Feb 24, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24526180). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.85 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.52 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046131 /PMID: 17551081 /3billion dataset). 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: 23958653, 24526180). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 23958653). A different missense change at the same codon (p.Ala306Val) has been reported to be associated with TMPRSS3 related disorder (ClinVar ID: VCV002445668). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2021

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified in compound heterozygosity with another variant in the same gene in a male patient with prelingual bilateral severe hearing loss -

Jun 10, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Pathogenic by Deafness Variation Datatbase -

Sep 06, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the TMPRSS3 c.916G>A (p.Ala306Thr) variant has been identified in a homozygous state in two siblings and in a compound heterozygous state in 15 individuals from nine families with autosomal recessive hearing loss (Elbracht et al. 2007; Weegerink et al. 2011; Lee et al. 2013; Chung et al. 2014; Gao et al. 2017). The variant was also found in a heterozygous state in at least three family members with normal hearing. Co-segregation of the variant with disease was demonstrated in at least one family (Gao et al. 2017), and has been suggested to be a founder variant in the Korean population, as two families with the variant were found to share the same haplotype (Chung et al. 2014). The p.Ala306Thr variant was absent from 1770 control chromosomes and is reported at a frequency of 0.00104 in the East Asian population of the Exome Aggregation Consortium. An in vitro yeast-based protease assay showed that the p.Ala306Thr variant-containing protein exhibited significantly reduced protease activity compared to the wild type protein as well as proteins containing other missense variants, consistent with the location of the variant near the Asp304 active site (Chung et al. 2014). Based on the collective evidence, the p.Ala306Thr 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. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP1+PP3_Moderate+PM2_Supporting -

not provided Pathogenic:6

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 06, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a significant defect in protease activity compared to wild type (PMID: 24526180); 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: 34416374, 21786053, 23958653, 17551081, 31045651, 31980526, 31589614, 35961784, 35062939, 34599368, 34868270, 28695016, 34519870, 24526180, 23208854, 36871673, 34599366, 22975204, 37147621, 31541171, 32238869, 34440452, 38102706, 34753855, 38819271, 31581539, 37244253, 38691166, 28246597) -

Apr 04, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 15, 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 threonine, which is neutral and polar, at codon 306 of the TMPRSS3 protein (p.Ala306Thr). This variant is present in population databases (rs181949335, gnomAD 0.06%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 17551081, 23208854, 24526180, 28246597, 28695016, 31045651). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Korean and Chinese ancestry (PMID: 24526180, 28695016). ClinVar contains an entry for this variant (Variation ID: 46131). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMPRSS3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2025

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 -

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 12, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala306Thr variant in TMPRSS3 has been reported in >10 individuals with autosomal recessive hearing loss and segregated in >10 affected relatives in >5 families (Elbracht 2007, Weegerink 2011, Schrauwen 2012, Lee 2013, Chung 2014, Gao 2017a, Gao 2017b). All affected individuals were either homozygous or compound heterozygous. This variant has also been identified in 0.06% (12/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support an impact on protein function (Chung 2014). Computational prediction tools and conservation analysis also support a functional impact. In summary, the p.Ala306Thr variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;D;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;.;T;T;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;M;M;.;M
PhyloP100		6.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	.;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.89, 0.89, 0.88, 0.91
MVP		0.96
MPC		0.52
ClinPred		0.89	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.94
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs181949335; hg19: chr21-43802210; COSMIC: COSV52305248;