21-42375852-G-A

Position:

chr21-42375852-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001256317.3(TMPRSS3):c.1208C>T(p.Pro403Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.17

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:

TMPRSS3 (HGNC:):

TMPRSS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a disulfide_bond (size 28) in uniprot entity TMPS3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001256317.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 21-42375852-G-A is Pathogenic according to our data. Variant chr21-42375852-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42375852-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.1208C>T	p.Pro403Leu	missense_variant	12/13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 linkuse as main transcript	c.1211C>T	p.Pro404Leu	missense_variant	12/13		NP_076927.1	P57727-1
TMPRSS3	NM_032404.3 linkuse as main transcript	c.830C>T	p.Pro277Leu	missense_variant	9/10		NP_115780.1	P57727-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 linkuse as main transcript	c.1208C>T	p.Pro403Leu	missense_variant	12/13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251368

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461528

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74146

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 404 of the TMPRSS3 protein (p.Pro404Leu). This variant is present in population databases (rs28939084, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 11462234, 31850270). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4945). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMPRSS3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TMPRSS3 function (PMID: 12920079). For these reasons, this variant has been classified as Pathogenic. -

Ear malformation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;D;D;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

.;H;H;.

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-9.3

.;.;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

.;.;D;D

Sift4G

Pathogenic

0.0

.;.;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.94, 0.94

MutPred

0.97

.;Gain of catalytic residue at P404 (P = 0.007);Gain of catalytic residue at P404 (P = 0.007);.;

MVP

0.98

MPC

0.53

ClinPred

1.0

GERP RS

5.1

Varity_R

0.95

gMVP

0.97

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