rs45598239

Variant names:

• chr21-42388983-C-T
• rs45598239
• NM_001256317.3:c.268G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.268G>A​(p.Ala90Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0447 in 1,614,130 control chromosomes in the GnomAD database, including 1,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (124 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1793 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.28
• Publications: 19 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: Benign. The variant received -19 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037552118).
• BP6: Variant 21-42388983-C-T is Benign according to our data. Variant chr21-42388983-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.268G>A	p.Ala90Thr	missense_variant	Exon 4 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.268G>A	p.Ala90Thr	missense_variant	Exon 4 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.268G>A	p.Ala90Thr	missense_variant	Exon 4 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.-114G>A		5_prime_UTR_variant	Exon 1 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.268G>A	p.Ala90Thr	missense_variant	Exon 4 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4946 AN: 152208 Hom.: 124 Cov.: 33

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0318 AC: 7990 AN: 251426 AF XY: 0.0320

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0520

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0459 AC: 67147 AN: 1461804 Hom.: 1793 Cov.: 33 AF XY: 0.0447 AC XY: 32521 AN XY: 727196

African (AFR) AF: 0.00648 AC: 217 AN: 33480

American (AMR) AF: 0.0154 AC: 690 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 646 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.00610 AC: 526 AN: 86258

European-Finnish (FIN) AF: 0.0408 AC: 2179 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0545 AC: 60562 AN: 1111932

Other (OTH) AF: 0.0380 AC: 2294 AN: 60396

GnomAD4 genome AF: 0.0325 AC: 4945 AN: 152326 Hom.: 124 Cov.: 33 AF XY: 0.0306 AC XY: 2283 AN XY: 74488

African (AFR) AF: 0.00765 AC: 318 AN: 41576

American (AMR) AF: 0.0185 AC: 283 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.0331 AC: 351 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0541 AC: 3681 AN: 68036

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.0467 Hom.: 644

Bravo AF: 0.0310

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0483 AC: 415

ExAC AF: 0.0330 AC: 4003

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0472

EpiControl AF: 0.0469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala90Thr in exon 4 of TMPRSS3: This variant has been identified in 4/178 (2.2%) probands with hearing loss (Rehm, unpublished data; Hutchin 2005) and was absent from 165 controls. However, in all 4 probands, a second variant was not identif ied. In addition, this variant has been identified in several control studies (r s45598239 ? 4 submissions) including 2/10 controls in our laboratory. In summary , this data suggests that the variant is benign. -

Sep 08, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 16, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:3

May 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;.;D;D;D
MetaRNN	Benign	0.0038	T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M
PhyloP100		4.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	.;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.60	.;T;T;T;T
Sift4G	Benign	0.54	.;T;T;T;T
Polyphen		0.98	D;D;D;.;D
Vest4		0.24, 0.21, 0.50
MPC		0.48
ClinPred		0.038	T
GERP RS		5.2
Varity_R		0.10
gMVP		0.64
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45598239; hg19: chr21-43809092;