21-42388518-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_001256317.3(TMPRSS3):c.331G>A(p.Gly111Ser) variant causes a missense change. The variant allele was found at a frequency of 0.109 in 1,614,026 control chromosomes in the GnomAD database, including 10,204 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G111G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1141 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9063 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.82

Publications

22 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 -17 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001256317.3

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=0.0025500655).

BP6

Variant 21-42388518-C-T is Benign according to our data. Variant chr21-42388518-C-T is described in ClinVar as Benign. ClinVar VariationId is 46115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMPRSS3	NM_001256317.3 link	c.331G>A	p.Gly111Ser	missense_variant	Exon 5 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4 link	c.331G>A	p.Gly111Ser	missense_variant	Exon 5 of 13		NP_076927.1
TMPRSS3	NM_032405.2 link	c.331G>A	p.Gly111Ser	missense_variant	Exon 5 of 9		NP_115781.1
TMPRSS3	NM_032404.3 link	c.-51G>A		5_prime_UTR_variant	Exon 2 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.331G>A	p.Gly111Ser	missense_variant	Exon 5 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17995

AN:

152054

Hom.:

1138

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.0823

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.120

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.0936

AC:

23532

AN:

251344

AF XY:

0.0925

show subpopulations

Gnomad AFR exome

AF:

0.151

Gnomad AMR exome

AF:

0.0656

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0877

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.108

AC:

157465

AN:

1461854

Hom.:

9063

Cov.:

AF XY:

0.107

AC XY:

77635

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.154

AC:

5166

AN:

33480

American (AMR)

AF:

0.0690

AC:

3084

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

3210

AN:

26134

East Asian (EAS)

AF:

0.000378

AC:

AN:

39686

South Asian (SAS)

AF:

0.0464

AC:

3999

AN:

86258

European-Finnish (FIN)

AF:

0.0919

AC:

4908

AN:

53418

Middle Eastern (MID)

AF:

0.130

AC:

748

AN:

5768

European-Non Finnish (NFE)

AF:

0.117

AC:

129879

AN:

1111994

Other (OTH)

AF:

0.107

AC:

6456

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

8657

17314

25970

34627

43284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4532

9064

13596

18128

22660

<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:

0.118

AC:

18011

AN:

152172

Hom.:

1141

Cov.:

AF XY:

0.115

AC XY:

8533

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.156

AC:

6463

AN:

41484

American (AMR)

AF:

0.103

AC:

1578

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

451

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.0367

AC:

177

AN:

4824

European-Finnish (FIN)

AF:

0.0823

AC:

871

AN:

10584

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.120

AC:

8146

AN:

68016

Other (OTH)

AF:

0.127

AC:

268

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

814

1628

2443

3257

4071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<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:

0.118

Hom.:

2639

Bravo

AF:

0.121

TwinsUK

AF:

0.114

AC:

422

ALSPAC

AF:

0.115

AC:

443

ESP6500AA

AF:

0.156

AC:

688

ESP6500EA

AF:

0.118

AC:

1011

ExAC

AF:

0.0976

AC:

11853

Asia WGS

AF:

0.0360

AC:

127

AN:

3478

EpiCase

AF:

0.118

EpiControl

AF:

0.123

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 8

Benign:1

Jan 13, 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

0.051

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.058

.;T;T;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.12

T;.;T;T;T

MetaRNN

Benign

0.0026

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.7

N;N;N;.;N

PhyloP100

4.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

1.7

.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.57

.;T;T;T;T

Sift4G

Benign

0.87

.;T;T;T;T

Polyphen

0.0

B;B;B;.;B

Vest4

0.16, 0.15, 0.14, 0.33

MPC

0.10

ClinPred

0.013

GERP RS

4.9

Varity_R

0.071

gMVP

0.47

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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