21-42388436-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1 PM2 PP5_Very_Strong BP4

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:25
• Conservation: PhyloP100: 5.34

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 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-42388436-G-T is Pathogenic according to our data. Variant chr21-42388436-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 46119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42388436-G-T is described in Lovd as [Likely_pathogenic]. Variant chr21-42388436-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.09016231).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.413C>A	p.Ala138Glu	missense_variant	5/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.413C>A	p.Ala138Glu	missense_variant	5/13
TMPRSS3	NM_032405.2	c.413C>A	p.Ala138Glu	missense_variant	5/9
TMPRSS3	NM_032404.3	c.32C>A	p.Ala11Glu	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.413C>A	p.Ala138Glu	missense_variant	5/13		NM_001256317.3	A1

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

GnomAD3 exomes AF: 0.000919 AC: 231 AN: 251450 Hom.: 0 AF XY: 0.000912 AC XY: 124 AN XY: 135910

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00137

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

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00160 Hom.: 1

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:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	case-control	Genetics Laboratory, Department of Biology, Semnan University	Aug 01, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 01, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 11, 2021	- -
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	Illumina Laboratory Services, Illumina	Mar 20, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2020	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. -
Pathogenic, criteria provided, single submitter	research	Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	-	in compound heterozygosis with the c.346G>A variant in a subject with non-syndromic sensorineural postlingual progressive hearing loss (sporadic) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	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. -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TMPRSS3: PM3:Very Strong, PM2, PP1, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
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	Mayo Clinic Laboratories, Mayo Clinic	May 31, 2022	PP1_strong, PM3_very_strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2023	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, 21786053, 22975204, 28566687, 29431110, 31053783, 28695016, 31589614, 36147510, 34868270, 34599368, 34758253, 31980526, 35580552, 35052694) -
Likely 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	Invitae	Jan 31, 2024	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). 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) has been performed at Invitae 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kariminejad - Najmabadi Pathology & Genetics Center	Jul 10, 2021	- -

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 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

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 31, 2016

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. -

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
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
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.43	T
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

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

Other links and lift over

dbSNP: rs147231991; hg19: chr21-43808545;