rs115489719

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000398397.3(TMPRSS3):c.969A>G(p.Leu323Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,164 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 25 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 17 hom. )

Consequence

TMPRSS3
ENST00000398397.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.73

Publications

2 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=-0.92).

BP6

Variant 21-42382048-T-C is Benign according to our data. Variant chr21-42382048-T-C is described in ClinVar as Benign. ClinVar VariationId is 46133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.73 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0098 (1492/152276) while in subpopulation AFR AF = 0.0332 (1380/41544). AF 95% confidence interval is 0.0318. There are 25 homozygotes in GnomAd4. There are 696 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.952+17A>G		intron_variant	Intron 9 of 12	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_032405.2 link	c.969A>G	p.Leu323Leu	synonymous_variant	Exon 9 of 9		NP_115781.1	P57727-3
TMPRSS3	NM_024022.4 link	c.952+17A>G		intron_variant	Intron 9 of 12		NP_076927.1	P57727-1
TMPRSS3	NM_032404.3 link	c.571+17A>G		intron_variant	Intron 6 of 9		NP_115780.1	P57727-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.952+17A>G		intron_variant	Intron 9 of 12		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.00976

AC:

1485

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00308

AC:

766

AN:

249058

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.0357

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000458

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00129

AC:

1888

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

834

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0360

AC:

1206

AN:

33478

American (AMR)

AF:

0.00257

AC:

115

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000292

AC:

325

AN:

1112010

Other (OTH)

AF:

0.00298

AC:

180

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

117

235

352

470

587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.00980

AC:

1492

AN:

152276

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

696

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0332

AC:

1380

AN:

41544

American (AMR)

AF:

0.00445

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00231

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68018

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

134

200

267

334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00472

Hom.:

Bravo

AF:

0.0113

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu323Leu in Exon 09 of TMPRSS3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 3.4% (126/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs115489719). -

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

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

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

-0.92

CADD

Benign

0.0020

(source)

DANN

Benign

0.38

PhyloP100

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(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