21-42385528-C-T

Variant names:

• chr21-42385528-C-T
• rs2839501
• NM_001256317.3:c.453G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256317.3(TMPRSS3):​c.453G>A​(p.Val151Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,612,724 control chromosomes in the GnomAD database, including 121,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20835 hom., cov: 32)
  • Exomes 𝑓: 0.36 (100230 hom.)
• Consequence: TMPRSS3 NM_001256317.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 21-42385528-C-T is Benign according to our data. Variant chr21-42385528-C-T is described in ClinVar as [Benign]. Clinvar id is 46122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42385528-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.72G>A	p.Val24Val	synonymous_variant	Exon 3 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.453G>A	p.Val151Val	synonymous_variant	Exon 6 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72603 AN: 151956 Hom.: 20783 Cov.: 32

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.473

GnomAD3 exomes AF: 0.360 AC: 90420 AN: 251436 Hom.: 18239 AF XY: 0.352 AC XY: 47819 AN XY: 135906

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.267

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.362 AC: 528370 AN: 1460650 Hom.: 100230 Cov.: 44 AF XY: 0.359 AC XY: 260652 AN XY: 726732

Gnomad4 AFR exome AF: 0.829

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.285

Gnomad4 NFE exome AF: 0.359

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.478 AC: 72716 AN: 152074 Hom.: 20835 Cov.: 32 AF XY: 0.469 AC XY: 34850 AN XY: 74314

Gnomad4 AFR AF: 0.811

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.280

Gnomad4 NFE AF: 0.357

Gnomad4 OTH AF: 0.478

Alfa AF: 0.388 Hom.: 15914

Bravo AF: 0.500

Asia WGS AF: 0.356 AC: 1241 AN: 3478

EpiCase AF: 0.359

EpiControl AF: 0.366

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Feb 16, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.19
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs2839501; hg19: chr21-43805637; COSMIC: COSV52302894; COSMIC: COSV52302894;