NM_001256317.3:c.453G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001256317.3(TMPRSS3):c.453G>A(p.Val151Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,612,724 control chromosomes in the GnomAD database, including 121,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 20835 hom., cov: 32)

Exomes 𝑓: 0.36 ( 100230 hom. )

Consequence

TMPRSS3
NM_001256317.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.09

Publications

33 publications found

Variant links:

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

TMPRSS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 21-42385528-C-T is Benign according to our data. Variant chr21-42385528-C-T is described in ClinVar as Benign. ClinVar VariationId is 46122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 link	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 13		NP_076927.1	P57727-1
TMPRSS3	NM_032405.2 link	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 9		NP_115781.1	P57727-3
TMPRSS3	NM_032404.3 link	c.72G>A	p.Val24Val	synonymous_variant	Exon 3 of 10		NP_115780.1	P57727-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.478

AC:

72603

AN:

151956

Hom.:

20783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.811

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.412

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.281

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.528

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.473

GnomAD2 exomes

AF:

0.360

AC:

90420

AN:

251436

AF XY:

0.352

show subpopulations

Gnomad AFR exome

AF:

0.823

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.267

Gnomad FIN exome

AF:

0.281

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.362

AC:

528370

AN:

1460650

Hom.:

100230

Cov.:

AF XY:

0.359

AC XY:

260652

AN XY:

726732

show subpopulations

African (AFR)

AF:

0.829

AC:

27733

AN:

33458

American (AMR)

AF:

0.312

AC:

13953

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.371

AC:

9690

AN:

26128

East Asian (EAS)

AF:

0.274

AC:

10862

AN:

39672

South Asian (SAS)

AF:

0.300

AC:

25833

AN:

86228

European-Finnish (FIN)

AF:

0.285

AC:

15210

AN:

53380

Middle Eastern (MID)

AF:

0.409

AC:

2356

AN:

5766

European-Non Finnish (NFE)

AF:

0.359

AC:

399356

AN:

1110946

Other (OTH)

AF:

0.387

AC:

23377

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

19604

39208

58812

78416

98020

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12778

25556

38334

51112

63890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.478

AC:

72716

AN:

152074

Hom.:

20835

Cov.:

AF XY:

0.469

AC XY:

34850

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.811

AC:

33649

AN:

41496

American (AMR)

AF:

0.412

AC:

6301

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1318

AN:

3472

East Asian (EAS)

AF:

0.281

AC:

1446

AN:

5152

South Asian (SAS)

AF:

0.283

AC:

1362

AN:

4816

European-Finnish (FIN)

AF:

0.280

AC:

2956

AN:

10574

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.357

AC:

24255

AN:

67954

Other (OTH)

AF:

0.478

AC:

1007

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1622

3244

4865

6487

8109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

594

1188

1782

2376

2970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.401

Hom.:

20639

Bravo

AF:

0.500

Asia WGS

AF:

0.356

AC:

1241

AN:

3478

EpiCase

AF:

0.359

EpiControl

AF:

0.366

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 8

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.19

(source)

DANN

Benign

0.54

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over