rs8130564

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256317.3(TMPRSS3):c.447-13A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.76

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 -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 id is 46121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42385547-T-C is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.447-13A>G	splice_polypyrimidine_tract_variant, intron_variant	ENST00000644384.2
TMPRSS3	NM_024022.4 linkuse as main transcript	c.447-13A>G	splice_polypyrimidine_tract_variant, intron_variant
TMPRSS3	NM_032404.3 linkuse as main transcript	c.66-13A>G	splice_polypyrimidine_tract_variant, intron_variant
TMPRSS3	NM_032405.2 linkuse as main transcript	c.447-13A>G	splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2 linkuse as main transcript	c.447-13A>G		splice_polypyrimidine_tract_variant, intron_variant			NM_001256317.3	A1	P57727-5

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

GnomAD3 exomes

AF:

0.477

AC:

119974

AN:

251424

Hom.:

30288

AF XY:

0.474

AC XY:

64379

AN XY:

135890

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 SAS exome

AF:

0.513

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

Gnomad4 AFR exome

AF:

0.882

Gnomad4 AMR exome

AF:

0.419

Gnomad4 ASJ exome

AF:

0.458

Gnomad4 EAS exome

AF:

0.592

Gnomad4 SAS exome

AF:

0.514

Gnomad4 FIN exome

AF:

0.366

Gnomad4 NFE exome

AF:

0.438

Gnomad4 OTH exome

AF:

0.489

GnomAD4 genome

AF:

0.564

AC:

85733

AN:

152092

Hom.:

26997

Cov.:

AF XY:

0.558

AC XY:

41500

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.864

Gnomad4 AMR

AF:

0.502

Gnomad4 ASJ

AF:

0.457

Gnomad4 EAS

AF:

0.596

Gnomad4 SAS

AF:

0.514

Gnomad4 FIN

AF:

0.357

Gnomad4 NFE

AF:

0.436

Gnomad4 OTH

AF:

0.563

Alfa

AF:

0.463

Hom.:

29119

Bravo

AF:

0.585

Asia WGS

AF:

0.608

AC:

2116

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Autosomal recessive nonsyndromic hearing loss 8

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.0010

DANN

Benign

0.25

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