rs115223836

Variant names:

Variant summary

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

The NM_001256317.3(TMPRSS3):c.957G>C(p.Met319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,613,614 control chromosomes in the GnomAD database, including 4 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 0.0022 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.36

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 -11 ACMG points.

PM1

In a disulfide_bond (size 117) in uniprot entity TMPS3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001256317.3

BP4

Computational evidence support a benign effect (MetaRNN=0.008906752).

BP6

Variant 21-42380208-C-G is Benign according to our data. Variant chr21-42380208-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178548.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00221 (337/152300) while in subpopulation AFR AF= 0.00775 (322/41574). AF 95% confidence interval is 0.00705. There are 3 homozygotes in gnomad4. There are 154 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.957G>C	p.Met319Ile	missense_variant	Exon 10 of 13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 link	c.957G>C	p.Met319Ile	missense_variant	Exon 10 of 13		NP_076927.1	P57727-1
TMPRSS3	NM_032404.3 link	c.576G>C	p.Met192Ile	missense_variant	Exon 7 of 10		NP_115780.1	P57727-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 link	c.957G>C	p.Met319Ile	missense_variant	Exon 10 of 13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

331

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00762

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000561

AC:

141

AN:

251136

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00801

Gnomad AMR exome

AF:

0.000203

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:

0.00000880

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000216

AC:

315

AN:

1461314

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

726988

show subpopulations

Gnomad4 AFR exome

AF:

0.00768

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.00221

AC:

337

AN:

152300

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00775

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.00225

ESP6500AA

AF:

0.00658

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Feb 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.957G>C (p.M319I) alteration is located in exon 10 (coding exon 9) of the TMPRSS3 gene. This alteration results from a G to C substitution at nucleotide position 957, causing the methionine (M) at amino acid position 319 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Met319Ile in Exon 10 of TMPRSS3: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (23/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs115223836). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.14

.;T;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.27

T;.;T;T

MetaRNN

Benign

0.0089

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.18

N;N;N;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.0

.;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.41

.;T;T;T

Sift4G

Benign

0.46

.;T;T;T

Polyphen

0.011

B;B;B;B

Vest4

0.30, 0.30, 0.30

MutPred

0.55

Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);.;

MVP

0.60

MPC

0.12

ClinPred

0.0017

GERP RS

3.6

Varity_R

0.16

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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