rs373058706

Positions:

chr21-42388941-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001256317.3(TMPRSS3):c.310G>A(p.Glu104Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,852 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: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.15

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 21-42388941-C-T is Pathogenic according to our data. Variant chr21-42388941-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42388941-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.310G>A	p.Glu104Lys	missense_variant	4/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4 linkuse as main transcript	c.310G>A	p.Glu104Lys	missense_variant	4/13		NP_076927.1
TMPRSS3	NM_032405.2 linkuse as main transcript	c.310G>A	p.Glu104Lys	missense_variant	4/9		NP_115781.1
TMPRSS3	NM_032404.3 linkuse as main transcript	c.-72G>A		5_prime_UTR_variant	1/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 linkuse as main transcript	c.310G>A	p.Glu104Lys	missense_variant	4/13		NM_001256317.3	ENSP00000494414	A1	P57727-5

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152232

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:

0.00000795

AC:

AN:

251460

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

0.0000137

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

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

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

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, criteria provided, single submitter

clinical testing

The Shared Resource Centre "Genome", Research Centre for Medical Genetics

Nov 10, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Feb 17, 2023

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 02, 2016

The p.Glu104Lys variant in TMPRSS3 has been reported in the homozygous state in 1 Pakistani individual with hearing loss and segregated in 6 affected relatives whose parents were consanguineous (Lee 2012). This variant has been identified i n 2/66672 of European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs373058706); however, its frequency is low e nough to be consistent with a recessive carrier frequency. In summary, although additional studies are required to fully establish its clinical significance, t his variant is likely pathogenic for autosomal recessive nonsyndromic hearing lo ss. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

.;D;D;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;H;.;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

.;D;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Uncertain

0.053

.;T;T;T;D

Polyphen

1.0

D;D;D;.;D

Vest4

0.93, 0.93, 0.93

MVP

0.98

MPC

0.54

ClinPred

1.0

GERP RS

5.1

Varity_R

0.97

gMVP

0.99

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