chr21-42383199-C-CTA

Variant names:

• chr21-42383199-C-CTA
• rs34966432
• NM_001256317.3:c.617-3_617-2dupTA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.617-3_617-2dupTA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0958 in 1,613,862 control chromosomes in the GnomAD database, including 9,652 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1028 hom., cov: 31)
  • Exomes 𝑓: 0.095 (8624 hom.)
• Consequence: TMPRSS3 NM_001256317.3 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.11
• Publications: 10 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 -12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12187959 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of 0 (no position change), new splice context is: ctttgttcccctccatatAGcct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 21-42383199-C-CTA is Benign according to our data. Variant chr21-42383199-C-CTA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	NM_001256317.3	MANE Select	c.617-3_617-2dupTA		splice_acceptor intron	N/A	NP_001243246.1
	TMPRSS3	NM_024022.4		c.617-3_617-2dupTA		splice_acceptor intron	N/A	NP_076927.1
	TMPRSS3	NM_032405.2		c.617-3_617-2dupTA		splice_acceptor intron	N/A	NP_115781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.617-3_617-2dupTA		splice_acceptor intron	N/A	ENSP00000494414.1
	TMPRSS3	ENST00000433957.7	TSL:1	c.617-3_617-2dupTA		splice_acceptor intron	N/A	ENSP00000411013.3
	TMPRSS3	ENST00000398397.3	TSL:1	c.617-3_617-2dupTA		splice_acceptor intron	N/A	ENSP00000381434.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15793 AN: 152132 Hom.: 1030 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0771

Gnomad OTH AF: 0.0999

GnomAD2 exomes AF: 0.120 AC: 30217 AN: 250988 AF XY: 0.123

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0868

Gnomad EAS exome AF: 0.309

Gnomad FIN exome AF: 0.0778

Gnomad NFE exome AF: 0.0784

Gnomad OTH exome AF: 0.0951

GnomAD4 exome AF: 0.0950 AC: 138825 AN: 1461612 Hom.: 8624 Cov.: 32 AF XY: 0.0982 AC XY: 71386 AN XY: 727102

African (AFR) AF: 0.124 AC: 4166 AN: 33472

American (AMR) AF: 0.107 AC: 4805 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 2236 AN: 26134

East Asian (EAS) AF: 0.314 AC: 12460 AN: 39688

South Asian (SAS) AF: 0.213 AC: 18397 AN: 86236

European-Finnish (FIN) AF: 0.0803 AC: 4282 AN: 53346

Middle Eastern (MID) AF: 0.104 AC: 600 AN: 5768

European-Non Finnish (NFE) AF: 0.0770 AC: 85589 AN: 1111878

Other (OTH) AF: 0.104 AC: 6290 AN: 60380

GnomAD4 genome AF: 0.104 AC: 15815 AN: 152250 Hom.: 1028 Cov.: 31 AF XY: 0.107 AC XY: 7929 AN XY: 74434

African (AFR) AF: 0.123 AC: 5096 AN: 41550

American (AMR) AF: 0.0942 AC: 1442 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 267 AN: 3470

East Asian (EAS) AF: 0.305 AC: 1573 AN: 5150

South Asian (SAS) AF: 0.232 AC: 1118 AN: 4826

European-Finnish (FIN) AF: 0.0759 AC: 806 AN: 10614

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0771 AC: 5242 AN: 68012

Other (OTH) AF: 0.0998 AC: 211 AN: 2114

Alfa AF: 0.0853 Hom.: 119

Bravo AF: 0.106

Asia WGS AF: 0.265 AC: 920 AN: 3478

EpiCase AF: 0.0802

EpiControl AF: 0.0779

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Feb 16, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 26, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 15, 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.

Autosomal recessive nonsyndromic hearing loss 8 Benign:1

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hearing loss, autosomal recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34966432; hg19: chr21-43803308; COSMIC: COSV52308624; COSMIC: COSV52308624;