21-42375754-C-T

Position:

chr21-42375754-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001256317.3(TMPRSS3):c.1306G>A(p.Val436Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,613,780 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 6 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 6 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.479

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 Benign. Variant got -11 ACMG points.

PM1

In a domain Peptidase S1 (size 232) in uniprot entity TMPS3_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_001256317.3

BP4

Computational evidence support a benign effect (MetaRNN=0.008411437).

BP6

Variant 21-42375754-C-T is Benign according to our data. Variant chr21-42375754-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46103.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00403 (614/152248) while in subpopulation AFR AF= 0.0141 (584/41540). AF 95% confidence interval is 0.0131. There are 6 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.1306G>A	p.Val436Ile	missense_variant	12/13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 linkuse as main transcript	c.1309G>A	p.Val437Ile	missense_variant	12/13		NP_076927.1	P57727-1
TMPRSS3	NM_032404.3 linkuse as main transcript	c.928G>A	p.Val310Ile	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.1306G>A	p.Val436Ile	missense_variant	12/13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.00398

AC:

605

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.0000735

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.000955

AC:

240

AN:

251382

Hom.:

AF XY:

0.000640

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0134

Gnomad AMR exome

AF:

0.000492

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:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000409

AC:

598

AN:

1461532

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

253

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0148

Gnomad4 AMR exome

AF:

0.000514

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.00403

AC:

614

AN:

152248

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000505

Hom.:

Bravo

AF:

0.00445

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Autosomal recessive nonsyndromic hearing loss 8

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 14, 2012

Val437Ile in Exon 12 of TMPRSS3: This variant is not expected to have clinical s ignificance because it has been identified in 1.3% (48/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs114904237). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

6.5

DANN

Benign

0.95

DEOGEN2

Benign

0.25

.;T;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.74

T;.;T;T

MetaRNN

Benign

0.0084

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.3

.;L;L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.35

.;.;N;N

REVEL

Benign

0.27

Sift

Benign

0.49

.;.;T;T

Sift4G

Benign

0.60

.;.;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.24, 0.24

MVP

0.36

MPC

0.085

ClinPred

0.0013

GERP RS

2.6

Varity_R

0.031

gMVP

0.58

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