rs139805921

Positions:

• chr21-42388935-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_001256317.3(TMPRSS3):​c.316C>T​(p.Arg106Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,613,668 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R106H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.85

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 12 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, 4 uncertain in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-42388935-G-A is Pathogenic according to our data. Variant chr21-42388935-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 381714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42388935-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-42388935-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.316C>T	p.Arg106Cys	missense_variant	4/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.316C>T	p.Arg106Cys	missense_variant	4/13
TMPRSS3	NM_032405.2	c.316C>T	p.Arg106Cys	missense_variant	4/9
TMPRSS3	NM_032404.3	c.-66C>T		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.316C>T	p.Arg106Cys	missense_variant	4/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251448 Hom.: 1 AF XY: 0.000280 AC XY: 38 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000380 AC: 555 AN: 1461366 Hom.: 1 Cov.: 32 AF XY: 0.000374 AC XY: 272 AN XY: 727028

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000428

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74472

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 106 of the TMPRSS3 protein (p.Arg106Cys). This variant is present in population databases (rs139805921, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with deafness (PMID: 23967202, 28246597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381714). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely 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: 27627659, 23967202, 28695016, 28246597, 34426522, 31589614, 34795337, 34868270, 36147510, 37331337) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TMPRSS3: PM3:Very Strong, PM2 -

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jul 29, 2020

Variant summary: TMPRSS3 c.316C>T (p.Arg106Cys) results in a non-conservative amino acid change located in the scavenger receptor cysteine-rich (SRCR) domain (IPR001190); most SRCR domains have six to eight cysteines that participate in intradomain disulfide bonds (InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251448 control chromosomes in the gnomAD database, including 1 homozygote. The variant, c.316C>T, has been reported in the literature in individuals affected with late onset hearing loss (Gao_2017, Miyagawa_2013), including a large Chinese family, where the variant in combination with a presumed severe mutation in trans (c.916G>A (p.Ala306Thr)) resulted in a milder phenotype (Gao_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (n=1) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely 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_Supporting, PP3_Supporting -

TMPRSS3-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2023

The TMPRSS3 c.316C>T variant is predicted to result in the amino acid substitution p.Arg106Cys. This variant has been reported in individuals with late-onset hearing loss (Supplemental Table 2, Miyagawa et al. 2013. PubMed ID: 23967202). This variant has also been reported in the compound heterozygous state in individuals with post lingual, milder hearing impairments (Patients II:2, II:3, and II:5, Gao et al. 2017. PubMed ID: 28246597) and in the homozygous state in an individual with perilingual hearing loss (Pavlenkova et al. 2021. PubMed ID: 34795337). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/21-43809044-G-A). This variant is predicted to lead to a mild form of hearing loss and structural protein modeling suggesting that a homozygous p.Arg106Cys variant would lead to a subtle protein change or would be similar to that of wildtype protein (Gao et al. 2017. PubMed ID: 28246597). This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/381714/). Taken together, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	D;.;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.9	M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
Polyphen		1.0	D;D;D;.;D
Vest4		0.90, 0.87, 0.90, 0.81
MVP		0.98
MPC		0.55
ClinPred		0.72	D
GERP RS		4.2
Varity_R		0.47
gMVP		0.84

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: rs139805921; hg19: chr21-43809044;