chr21-42389975-C-T

Position:

chr21-42389975-C-T

Variant summary

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

The NM_001256317.3(TMPRSS3):c.157G>A(p.Val53Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0762 in 1,613,530 control chromosomes in the GnomAD database, including 5,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 595 hom., cov: 33)

Exomes 𝑓: 0.075 ( 5058 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.02

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 (MetaRNN=0.0013293326).

BP6

Variant 21-42389975-C-T is Benign according to our data. Variant chr21-42389975-C-T is described in ClinVar as [Benign]. Clinvar id is 46105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42389975-C-T is described in Lovd as [Benign]. Variant chr21-42389975-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.157G>A	p.Val53Ile	missense_variant	3/13	ENST00000644384.2
TMPRSS3	NM_024022.4 linkuse as main transcript	c.157G>A	p.Val53Ile	missense_variant	3/13
TMPRSS3	NM_032405.2 linkuse as main transcript	c.157G>A	p.Val53Ile	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2 linkuse as main transcript	c.157G>A	p.Val53Ile	missense_variant	3/13		NM_001256317.3	A1	P57727-5

Frequencies

GnomAD3 genomes

AF:

0.0841

AC:

12783

AN:

152086

Hom.:

597

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0960

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.0342

Gnomad FIN

AF:

0.0578

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0689

Gnomad OTH

AF:

0.0766

GnomAD3 exomes

AF:

0.0756

AC:

19019

AN:

251458

Hom.:

969

AF XY:

0.0704

AC XY:

9567

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.192

Gnomad SAS exome

AF:

0.0284

Gnomad FIN exome

AF:

0.0576

Gnomad NFE exome

AF:

0.0657

Gnomad OTH exome

AF:

0.0598

GnomAD4 exome

AF:

0.0754

AC:

110158

AN:

1461326

Hom.:

5058

Cov.:

AF XY:

0.0730

AC XY:

53084

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.101

Gnomad4 ASJ exome

AF:

0.0206

Gnomad4 EAS exome

AF:

0.239

Gnomad4 SAS exome

AF:

0.0295

Gnomad4 FIN exome

AF:

0.0580

Gnomad4 NFE exome

AF:

0.0735

Gnomad4 OTH exome

AF:

0.0726

GnomAD4 genome

AF:

0.0840

AC:

12781

AN:

152204

Hom.:

595

Cov.:

AF XY:

0.0825

AC XY:

6142

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.109

Gnomad4 AMR

AF:

0.0957

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.207

Gnomad4 SAS

AF:

0.0344

Gnomad4 FIN

AF:

0.0578

Gnomad4 NFE

AF:

0.0689

Gnomad4 OTH

AF:

0.0758

Alfa

AF:

0.0705

Hom.:

1121

Bravo

AF:

0.0884

TwinsUK

AF:

0.0742

AC:

275

ALSPAC

AF:

0.0729

AC:

281

ESP6500AA

AF:

0.110

AC:

484

ESP6500EA

AF:

0.0658

AC:

566

ExAC

AF:

0.0732

AC:

8886

Asia WGS

AF:

0.100

AC:

349

AN:

3478

EpiCase

AF:

0.0648

EpiControl

AF:

0.0642

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
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	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.060

.;T;T;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.64

T;.;T;T;T

MetaRNN

Benign

0.0013

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N;.;N

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.33

.;N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.074

.;T;T;T;T

Sift4G

Benign

0.25

.;T;T;T;T

Polyphen

0.035

B;B;B;.;B

Vest4

0.030, 0.028, 0.022, 0.074

MPC

0.090

ClinPred

0.0028

GERP RS

4.2

Varity_R

0.033

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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