21-42389975-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001256317.3(TMPRSS3):c.157G>A(p.Val53Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0762 in 1,613,530 control chromosomes in the GnomAD database, including 5,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 595 hom., cov: 33)

Exomes 𝑓: 0.075 ( 5058 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.02

Publications

24 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 -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=0.0013293326).

BP6

Variant 21-42389975-C-T is Benign according to our data. Variant chr21-42389975-C-T is described in ClinVar as Benign. ClinVar VariationId is 46105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.157G>A	p.Val53Ile	missense_variant	Exon 3 of 13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 link	c.157G>A	p.Val53Ile	missense_variant	Exon 3 of 13		NP_076927.1	P57727-1
TMPRSS3	NM_032405.2 link	c.157G>A	p.Val53Ile	missense_variant	Exon 3 of 9		NP_115781.1	P57727-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.157G>A	p.Val53Ile	missense_variant	Exon 3 of 13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.0841

AC:

12783

AN:

152086

Hom.:

597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0960

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.0578

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0689

Gnomad OTH

AF:

0.0766

GnomAD2 exomes

AF:

0.0756

AC:

19019

AN:

251458

AF XY:

0.0704

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.192

Gnomad FIN exome

AF:

0.0576

Gnomad NFE exome

AF:

0.0657

Gnomad OTH exome

AF:

0.0598

GnomAD4 exome

AF:

0.0754

AC:

110158

AN:

1461326

Hom.:

5058

Cov.:

AF XY:

0.0730

AC XY:

53084

AN XY:

726984

show subpopulations

African (AFR)

AF:

0.111

AC:

3699

AN:

33472

American (AMR)

AF:

0.101

AC:

4505

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0206

AC:

539

AN:

26136

East Asian (EAS)

AF:

0.239

AC:

9487

AN:

39678

South Asian (SAS)

AF:

0.0295

AC:

2541

AN:

86250

European-Finnish (FIN)

AF:

0.0580

AC:

3095

AN:

53408

Middle Eastern (MID)

AF:

0.0340

AC:

196

AN:

5766

European-Non Finnish (NFE)

AF:

0.0735

AC:

81714

AN:

1111514

Other (OTH)

AF:

0.0726

AC:

4382

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

4850

9701

14551

19402

24252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3230

6460

9690

12920

16150

<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:

0.0840

AC:

12781

AN:

152204

Hom.:

595

Cov.:

AF XY:

0.0825

AC XY:

6142

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.109

AC:

4513

AN:

41512

American (AMR)

AF:

0.0957

AC:

1464

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.207

AC:

1075

AN:

5184

South Asian (SAS)

AF:

0.0344

AC:

166

AN:

4824

European-Finnish (FIN)

AF:

0.0578

AC:

612

AN:

10590

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0689

AC:

4687

AN:

68016

Other (OTH)

AF:

0.0758

AC:

160

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

607

1214

1820

2427

3034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0733

Hom.:

2225

Bravo

AF:

0.0884

TwinsUK

AF:

0.0742

AC:

275

ALSPAC

AF:

0.0729

AC:

281

ESP6500AA

AF:

0.110

AC:

484

ESP6500EA

AF:

0.0658

AC:

566

ExAC

AF:

0.0732

AC:

8886

Asia WGS

AF:

0.100

AC:

349

AN:

3478

EpiCase

AF:

0.0648

EpiControl

AF:

0.0642

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:2

Feb 03, 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

- -

Autosomal recessive nonsyndromic hearing loss 8

Benign:1

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.060

.;T;T;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.64

T;.;T;T;T

MetaRNN

Benign

0.0013

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N;.;N

PhyloP100

1.0

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.33

.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.074

.;T;T;T;T

Sift4G

Benign

0.25

.;T;T;T;T

Polyphen

0.035

B;B;B;.;B

Vest4

0.030, 0.028, 0.022, 0.074

MPC

0.090

ClinPred

0.0028

GERP RS

4.2

Varity_R

0.033

gMVP

0.65

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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