rs56264519

chr21-42375787-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PP5_Very_Strong

The NM_001256317.3(TMPRSS3):c.1273G>A(p.Ala425Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,730 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 7.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 28) in uniprot entity TMPS3_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_001256317.3
• PP5: Variant 21-42375787-C-T is Pathogenic according to our data. Variant chr21-42375787-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 46102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42375787-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-42375787-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.1273G>A	p.Ala425Thr	missense_variant	12/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.1276G>A	p.Ala426Thr	missense_variant	12/13
TMPRSS3	NM_032404.3	c.895G>A	p.Ala299Thr	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1273G>A	p.Ala425Thr	missense_variant	12/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152110 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000971 AC: 244 AN: 251402 Hom.: 0 AF XY: 0.000912 AC XY: 124 AN XY: 135904

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00158 AC: 2306 AN: 1461502 Hom.: 5 Cov.: 32 AF XY: 0.00148 AC XY: 1077 AN XY: 727062

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00188

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152228 Hom.: 1 Cov.: 31 AF XY: 0.00110 AC XY: 82 AN XY: 74430

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00169 Hom.: 2

Bravo AF: 0.00124

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.00202

EpiControl AF: 0.00207

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2022	PP1_strong, PM3_very_strong, PS3_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	TMPRSS3: PM3:Very Strong, PP1:Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 426 of the TMPRSS3 protein (p.Ala426Thr). This variant is present in population databases (rs56264519, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with nonsyndromic hearing loss (PMID: 21786053, 28566687, 29196752, 30242206). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ala425Thr. ClinVar contains an entry for this variant (Variation ID: 46102). 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 95%. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2020	The best available variant frequency is consistent with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Strong co-segregation with disease in affected individuals from a single family. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The TMPRSS3 p.A426T variant has been reported in multiple cases of hearing loss and was found to segregate with disease in five affected individuals from two families who were compound heterozygous for this variant and another pathogenic variant (Weegerink_2011_PMID:21786053, Oldak_2019_PMID:31412945; Lechowicz_2017_PMID:28566687). The variant was identified in dbSNP (ID: rs56264519), LOVD 3.0 and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine and as likely pathogenic by Fulgent Genetics, GeneDx, Knight Diagnostic Laboratories, EGL Genetic Diagnostics and Genetics Services Laboratory, University of Chicago). The variant was identified in control databases in 268 of 282764 chromosomes at a frequency of 0.0009478 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 187 of 129114 chromosomes (freq: 0.001448), Latino in 50 of 35432 chromosomes (freq: 0.001411), Other in 9 of 7220 chromosomes (freq: 0.001247), Ashkenazi Jewish in 5 of 10366 chromosomes (freq: 0.000482), African in 9 of 24950 chromosomes (freq: 0.000361), South Asian in 5 of 30616 chromosomes (freq: 0.000163) and European (Finnish) in 3 of 25116 chromosomes (freq: 0.000119), but was not observed in the East Asian population. The p.A426 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional analysis in yeast demonstrated that the p.A426T variant caused significantly reduced protein activity (Lee_2003_PMID: 12920079). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2023	Published functional studies suggest a damaging effect as the variant showed significantly diminished colony formation in a protease assay compared to wild-type (Lee et al., 2003); 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: 21786053, 11907649, 24526180, 21534946, 28263784, 30487145, 31412945, 34426522, 31980526, 30242206, 33297549, 31589614, 34652575, 32860223, 34599368, 34997062, 34171171, 28566687, Ozieblo_2022_IJMS, 29196752, 12920079, 33879512, 35961784, 34868270, 35682719) -

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	research	Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	-	in compound heterozygosis with the c.916G>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	Genetics and Molecular Pathology, SA Pathology	Jul 01, 2022	The TMPRSS3 c.1273G>A variant is classified as PATHOGENIC (PS3, PS4, PM3, PP1_moderate) The TMPRSS3 c.1273G>A variant is a single nucleotide change in exon 12/13 of the TMPRSS3 gene, which is predicted to change the amino acid alanine at position 425 in the protein to threonine. The variant has been reported in multiple individuals with a clinical presentation of Deafness, autosomal recessive 8/10 (MIM:601072) (PMID:21786053; PMID:31412945; PMID:28566687) (PS4). Published studies have shown this variant to co-segregate with disease in multiple families (PMID:21786053; PMID:31412945; PMID:28566687) (PP1_moderate). In vitro functional studies have shown this variant leads to reduced proteolytic activity of ~24% compared with WT (PMID:12920079) (PS3). This variant has been reported in dbSNP (rs56264519) and has been reported in population databases (163/152110, 1 homozygote). This variant has been reported in ClinVar as Pathogenic by other clinical laboratories (Variation ID: 46102) and as damaging for nonsyndromic hearing loss in the disease database HGMD (CM116227). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 25, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Jul 15, 2021

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria:The filtering allele frequency of c.1276G>A variant (p.A426T) in TMPRSS3 gene is 0.1% (187/129114 with 95% CI) in european non-finnish ethnic group obtanied from gnomAD population database, meeting BS1_Sup. This variant has been found in trans with 4 pathogenic/likely pathogenic variants in hearing impairment patients applying for PM3_VS (PMID: 21786053, 28566687, 29196752 and this report). There is one familial case with four sibling that showed high frequency hearing impairment with childhood onset and eight siblings with normal hearing. All the affected members had the A426T variant in trans with a pathogenic variant in TMPRSS3 gene while all the unaffected siblings carried only one variant or were wild type, applying to PP1_Strong (PMID: 21786053). A yeast based protease assay demonstrated that A426T mutatn possesed a significantly disminished protelotytic activity, PMID:12920079, PS3_Sup. Considering: BS1_Sup, PM3_VS, PP1_S and PS3_Sup, the c.1276G>A variant is classified as Pathogenic for autosomal recessive non-syndromic hearing loss. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 12, 2018

The p.Ala426Thr variant in TMPRSS3 has been reported in >10 individuals with hea ring loss, at least 4 of whom harbored a second pathogenic variant in TMPRSS3 (2 compound heterozygous occurences and 2 co-occurences with phase unknown; Watten hofer 2002, Weegerink 2011, Baux 2017, Lechowicz 2017, LMM data). Furthermore, t he p.Ala426Thr variant segregated with disease in 5 affected relatives from 2 fa milies (Weegerink 2011, LMM data). This variant has also been identified in 0.15 % (187/129114) of European chromosomes by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org); however, this frequency is low enough to b e consistent with a recessive carrier frequency. In vitro functional studies sup port an impact on protein function (Lee 2003). Finally, this variant has been re ported as Likely Pathogenic in ClinVar (Variation ID 46102). In summary, the p.A la426Thr variant meets criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner based upon biallelic case observations, segrega tion studies and functional evidence. ACMG/AMP Criteria applied: PM3_Strong, PP1 _Strong, PP3, PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
Polyphen		1.0	D;D;D;D
Vest4		0.91, 0.94
MVP		0.92
MPC		0.52
ClinPred		0.65	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.91

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: rs56264519; hg19: chr21-43795896;