chr21-42375788-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_001256317.3(TMPRSS3):c.1272C>T(p.Cys424Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,613,612 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

TMPRSS3
NM_001256317.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.210

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 8
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMPRSS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 21-42375788-G-A is Benign according to our data. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101. Variant chr21-42375788-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 46101.

BP7

Synonymous conserved (PhyloP=0.21 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3 link	c.1272C>T	p.Cys424Cys	synonymous_variant	Exon 12 of 13	ENST00000644384.2	NP_001243246.1	P57727-5
TMPRSS3	NM_024022.4 link	c.1275C>T	p.Cys425Cys	synonymous_variant	Exon 12 of 13		NP_076927.1	P57727-1
TMPRSS3	NM_032404.3 link	c.894C>T	p.Cys298Cys	synonymous_variant	Exon 9 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.1272C>T	p.Cys424Cys	synonymous_variant	Exon 12 of 13		NM_001256317.3	ENSP00000494414.1		P57727-5

Frequencies

GnomAD3 genomes

AF:

0.000395

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000414

AC:

104

AN:

250956

AF XY:

0.000390

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000713

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000444

AC:

649

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000459

AC XY:

334

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

52982

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000538

AC:

598

AN:

1112004

Other (OTH)

AF:

0.000215

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41542

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000780

AC:

AN:

67990

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000594

Hom.:

Bravo

AF:

0.000366

EpiCase

AF:

0.00104

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

May 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11907649) -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMPRSS3: BP4, BP7 -

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 8

Uncertain:1

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Mar 31, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cys425Cys in exon 12 of TMPRSS3: This variant was reported in 1 individual with hearing loss (Wattenhofer 2002). However, this variant is not expected to have c linical significance because it does not alter an amino acid residue, is not loc ated near a splice junction, and is listed in dbSNP (rs56178910). -

TMPRSS3-related disorder

Benign:1

Nov 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.5

(source)

DANN

Benign

0.57

PhyloP100

0.21

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over