21-42372760-C-T

Position:

chr21-42372760-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256317.3(TMPRSS3):c.*2G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,613,162 control chromosomes in the GnomAD database, including 44,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3547 hom., cov: 31)

Exomes 𝑓: 0.22 ( 40950 hom. )

Consequence

TMPRSS3
NM_001256317.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.324

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 21-42372760-C-T is Benign according to our data. Variant chr21-42372760-C-T is described in ClinVar as [Benign]. Clinvar id is 46089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42372760-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.*2G>A	3_prime_UTR_variant	13/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4 linkuse as main transcript	c.*2G>A	3_prime_UTR_variant	13/13		NP_076927.1
TMPRSS3	NM_032404.3 linkuse as main transcript	c.*2G>A	3_prime_UTR_variant	10/10		NP_115780.1

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28576

AN:

151908

Hom.:

3538

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.243

Gnomad EAS

AF:

0.560

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.245

GnomAD3 exomes

AF:

0.238

AC:

59947

AN:

251476

Hom.:

8869

AF XY:

0.248

AC XY:

33648

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.0725

Gnomad AMR exome

AF:

0.157

Gnomad ASJ exome

AF:

0.257

Gnomad EAS exome

AF:

0.566

Gnomad SAS exome

AF:

0.351

Gnomad FIN exome

AF:

0.189

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.235

GnomAD4 exome

AF:

0.225

AC:

328119

AN:

1461136

Hom.:

40950

Cov.:

AF XY:

0.229

AC XY:

166559

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.0687

Gnomad4 AMR exome

AF:

0.163

Gnomad4 ASJ exome

AF:

0.252

Gnomad4 EAS exome

AF:

0.543

Gnomad4 SAS exome

AF:

0.346

Gnomad4 FIN exome

AF:

0.189

Gnomad4 NFE exome

AF:

0.211

Gnomad4 OTH exome

AF:

0.246

GnomAD4 genome

AF:

0.188

AC:

28591

AN:

152026

Hom.:

3547

Cov.:

AF XY:

0.194

AC XY:

14383

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0717

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.243

Gnomad4 EAS

AF:

0.560

Gnomad4 SAS

AF:

0.361

Gnomad4 FIN

AF:

0.191

Gnomad4 NFE

AF:

0.210

Gnomad4 OTH

AF:

0.253

Alfa

AF:

0.210

Hom.:

8468

Bravo

AF:

0.184

Asia WGS

AF:

0.454

AC:

1576

AN:

3478

EpiCase

AF:

0.223

EpiControl

AF:

0.223

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 03, 2011	This variant is a high-frequency polymorphism (MAF up to 62%) recorded by dbSNP (rs13047838) in over 20 populations. It is also listed as a clinically-associate d, non-pathogenic variant. -

Autosomal recessive nonsyndromic hearing loss 8

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.5

DANN

Benign

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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