21-42372760-C-T

Variant names:

• chr21-42372760-C-T
• rs13047838
• ENST00000474596.5:n.1235G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000474596.5(TMPRSS3):​n.1235G>A variant causes a non coding transcript exon 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 ENST00000474596.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.324
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 46089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.*2G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.*2G>A		3_prime_UTR_variant	Exon 13 of 13		NP_076927.1
TMPRSS3	NM_032404.3	c.*2G>A		3_prime_UTR_variant	Exon 10 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.*2G>A		3_prime_UTR_variant	Exon 13 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28576 AN: 151908 Hom.: 3538 Cov.: 31

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

GnomAD2 exomes AF: 0.238 AC: 59947 AN: 251476 AF XY: 0.248

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 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.: 34 AF XY: 0.229 AC XY: 166559 AN XY: 726918

African (AFR) AF: 0.0687 AC: 2301 AN: 33472

American (AMR) AF: 0.163 AC: 7309 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 6588 AN: 26126

East Asian (EAS) AF: 0.543 AC: 21571 AN: 39690

South Asian (SAS) AF: 0.346 AC: 29824 AN: 86232

European-Finnish (FIN) AF: 0.189 AC: 10106 AN: 53402

Middle Eastern (MID) AF: 0.243 AC: 1403 AN: 5764

European-Non Finnish (NFE) AF: 0.211 AC: 234188 AN: 1111364

Other (OTH) AF: 0.246 AC: 14829 AN: 60366

GnomAD4 genome AF: 0.188 AC: 28591 AN: 152026 Hom.: 3547 Cov.: 31 AF XY: 0.194 AC XY: 14383 AN XY: 74324

African (AFR) AF: 0.0717 AC: 2974 AN: 41486

American (AMR) AF: 0.210 AC: 3204 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 842 AN: 3468

East Asian (EAS) AF: 0.560 AC: 2888 AN: 5154

South Asian (SAS) AF: 0.361 AC: 1742 AN: 4820

European-Finnish (FIN) AF: 0.191 AC: 2022 AN: 10570

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14237 AN: 67934

Other (OTH) AF: 0.253 AC: 534 AN: 2112

Alfa AF: 0.203 Hom.: 11687

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

Submissions by phenotype

not specified Benign:2

Jun 03, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

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 13, 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

May 09, 2017

GeneDx

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	-0.76
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13047838; hg19: chr21-43792869; COSMIC: COSV52303487;