rs181949335

Positions:

• chr21-42382101-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 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 (★★).

• 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:14
• Conservation: PhyloP100: 6.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a disulfide_bond (size 117) in uniprot entity TMPS3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 46131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42382101-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-42382101-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.916G>A	p.Ala306Thr	missense_variant	9/13		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

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 249060 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134822

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000250

Gnomad4 OTH exome AF: 0.0000497

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

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000238 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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM3_VeryStrong+PP1+PP3_Moderate+PM2_Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Feb 10, 2021	This variant was identified in compound heterozygosity with another variant in the same gene in a male patient with prelingual bilateral severe hearing loss -
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	research	Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	-	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) -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046131). 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). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 06, 2018	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. -

not provided Pathogenic:6

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	GeneDx	Dec 12, 2024	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, 23208854, 21786053, 28246597, 23958653, 17551081, 31045651, 31980526, 31589614, 35961784, 35062939, 34599368, 34868270, 28695016, 34519870, 24526180, 36871673) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TMPRSS3: PM3:Very Strong, PP1:Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2018	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	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. -

Hearing impairment Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 12, 2021

PS1_Strong, PM2_Moderate, PP3_Supporting -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 12, 2019

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs181949335; hg19: chr21-43802210; COSMIC: COSV52305248;