21-42385547-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256317.3(TMPRSS3):c.447-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,611,910 control chromosomes in the GnomAD database, including 183,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 26997 hom., cov: 32)

Exomes 𝑓: 0.46 ( 156711 hom. )

Consequence

TMPRSS3
NM_001256317.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.76

Publications

20 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 21-42385547-T-C is Benign according to our data. Variant chr21-42385547-T-C is described in ClinVar as Benign. ClinVar VariationId is 46121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
TMPRSS3	NM_001256317.3 link	c.447-13A>G	intron_variant	Intron 5 of 12	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4 link	c.447-13A>G	intron_variant	Intron 5 of 12		NP_076927.1
TMPRSS3	NM_032405.2 link	c.447-13A>G	intron_variant	Intron 5 of 8		NP_115781.1
TMPRSS3	NM_032404.3 link	c.66-13A>G	intron_variant	Intron 2 of 9		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.447-13A>G		intron_variant	Intron 5 of 12		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes

AF:

0.563

AC:

85622

AN:

151974

Hom.:

26947

Cov.:

show subpopulations

Gnomad AFR

AF:

0.864

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.457

Gnomad EAS

AF:

0.597

Gnomad SAS

AF:

0.513

Gnomad FIN

AF:

0.357

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.436

Gnomad OTH

AF:

0.558

GnomAD2 exomes

AF:

0.477

AC:

119974

AN:

251424

AF XY:

0.474

show subpopulations

Gnomad AFR exome

AF:

0.876

Gnomad AMR exome

AF:

0.409

Gnomad ASJ exome

AF:

0.464

Gnomad EAS exome

AF:

0.583

Gnomad FIN exome

AF:

0.360

Gnomad NFE exome

AF:

0.439

Gnomad OTH exome

AF:

0.459

GnomAD4 exome

AF:

0.457

AC:

666423

AN:

1459818

Hom.:

156711

Cov.:

AF XY:

0.457

AC XY:

331939

AN XY:

726302

show subpopulations

African (AFR)

AF:

0.882

AC:

29499

AN:

33456

American (AMR)

AF:

0.419

AC:

18718

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.458

AC:

11959

AN:

26122

East Asian (EAS)

AF:

0.592

AC:

23476

AN:

39672

South Asian (SAS)

AF:

0.514

AC:

44308

AN:

86218

European-Finnish (FIN)

AF:

0.366

AC:

19525

AN:

53308

Middle Eastern (MID)

AF:

0.514

AC:

2963

AN:

5764

European-Non Finnish (NFE)

AF:

0.438

AC:

486494

AN:

1110218

Other (OTH)

AF:

0.489

AC:

29481

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

20473

40945

61418

81890

102363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14950

29900

44850

59800

74750

<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:

0.564

AC:

85733

AN:

152092

Hom.:

26997

Cov.:

AF XY:

0.558

AC XY:

41500

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.864

AC:

35860

AN:

41518

American (AMR)

AF:

0.502

AC:

7679

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

1586

AN:

3468

East Asian (EAS)

AF:

0.596

AC:

3070

AN:

5152

South Asian (SAS)

AF:

0.514

AC:

2472

AN:

4814

European-Finnish (FIN)

AF:

0.357

AC:

3778

AN:

10580

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.436

AC:

29623

AN:

67954

Other (OTH)

AF:

0.563

AC:

1191

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1684

3368

5052

6736

8420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<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:

0.492

Hom.:

57059

Bravo

AF:

0.585

Asia WGS

AF:

0.608

AC:

2116

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 23, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

not provided

Benign:3

Dec 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:2

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

(source)

DANN

Benign

0.25

PhyloP100

-3.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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