21-42389039-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 3P and 10B. PM1PP2BP4_StrongBP6BS1BS2_Supporting

The NM_001256317.3(TMPRSS3):c.212T>C(p.Phe71Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000253 in 1,614,172 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F71F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

TMPRSS3
NM_001256317.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 5.04

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001256317.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 8, hearing loss, autosomal recessive.

BP4

Computational evidence support a benign effect (MetaRNN=0.008987516).

BP6

Variant 21-42389039-A-G is Benign according to our data. Variant chr21-42389039-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225495.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000335 (51/152360) while in subpopulation EAS AF = 0.00965 (50/5184). AF 95% confidence interval is 0.00752. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.212T>C	p.Phe71Ser	missense_variant	Exon 4 of 13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 link	c.212T>C	p.Phe71Ser	missense_variant	Exon 4 of 13		NP_076927.1	P57727-1
TMPRSS3	NM_032405.2 link	c.212T>C	p.Phe71Ser	missense_variant	Exon 4 of 9		NP_115781.1	P57727-3
TMPRSS3	NM_032404.3 link	c.-170T>C		5_prime_UTR_variant	Exon 1 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.212T>C	p.Phe71Ser	missense_variant	Exon 4 of 13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152242

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:

0.00962

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000748

AC:

188

AN:

251274

AF XY:

0.000721

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0100

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00829

AC:

329

AN:

39698

Gnomad4 SAS exome

AF:

0.0000580

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53360

Gnomad4 NFE exome

AF:

0.00000270

AC:

AN:

1111996

Gnomad4 Remaining exome

AF:

0.000315

AC:

AN:

60396

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000335

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00965

AC:

0.00964506

AN:

0.00964506

Gnomad4 SAS

AF:

0.000207

AC:

0.000206954

AN:

0.000206954

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.000457

ExAC

AF:

0.000749

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8

Uncertain:2

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:2

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23958653, 30245029, 25770132, 23967202) -

not specified

Benign:1

Mar 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Phe71Ser in exon 4 of TMPRSS3: This variant is not expected to have clinical s ignificance because it has been identified in 1.0% (90/8612) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs185332310). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

.;T;T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

D;.;D;D;T

MetaRNN

Benign

0.0090

T;T;T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

0.69

N;N;N;.;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.15

.;N;N;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.024

.;D;D;D;D

Sift4G

Benign

0.12

.;T;T;T;T

Polyphen

0.99

D;P;P;.;D

Vest4

0.70, 0.70, 0.70, 0.70

MVP

0.95

MPC

0.63

ClinPred

0.076

GERP RS

5.1

Varity_R

0.11

gMVP

0.85

Mutation Taster

=78/22

polymorphism

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