rs115489719

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_032405.2(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
NM_032405.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.73

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.00308

AC:

766

AN:

249058

Hom.:

AF XY:

0.00225

AC XY:

303

AN XY:

134822

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.0360

Gnomad4 AMR exome

AF:

0.00257

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000292

Gnomad4 OTH exome

AF:

0.00298

GnomAD4 genome

AF:

0.00980

AC:

1492

AN:

152276

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

696

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0332

Gnomad4 AMR

AF:

0.00445

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00803

Alfa

AF:

0.00481

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

Jan 30, 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

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

DANN

Benign

0.38

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over