21-42388417-T-C

Variant names:

• chr21-42388417-T-C
• rs61731564
• NM_001256317.3:c.432A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256317.3(TMPRSS3):​c.432A>G​(p.Gln144Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,614,210 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (109 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (86 hom.)
• Consequence: TMPRSS3 NM_001256317.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.31
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 21-42388417-T-C is Benign according to our data. Variant chr21-42388417-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0663 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.432A>G	p.Gln144Gln	synonymous	Exon 5 of 13	NP_001243246.1
	TMPRSS3	NM_024022.4		c.432A>G	p.Gln144Gln	synonymous	Exon 5 of 13	NP_076927.1
	TMPRSS3	NM_032405.2		c.432A>G	p.Gln144Gln	synonymous	Exon 5 of 9	NP_115781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.432A>G	p.Gln144Gln	synonymous	Exon 5 of 13	ENSP00000494414.1
	TMPRSS3	ENST00000433957.7	TSL:1	c.432A>G	p.Gln144Gln	synonymous	Exon 5 of 13	ENSP00000411013.3
	TMPRSS3	ENST00000398397.3	TSL:1	c.432A>G	p.Gln144Gln	synonymous	Exon 5 of 9	ENSP00000381434.3

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3014 AN: 152214 Hom.: 105 Cov.: 33

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00817

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00519 AC: 1305 AN: 251390 AF XY: 0.00371

Gnomad AFR exome AF: 0.0677

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00221 AC: 3224 AN: 1461878 Hom.: 86 Cov.: 31 AF XY: 0.00192 AC XY: 1399 AN XY: 727240

African (AFR) AF: 0.0671 AC: 2246 AN: 33480

American (AMR) AF: 0.00452 AC: 202 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000372 AC: 414 AN: 1112008

Other (OTH) AF: 0.00530 AC: 320 AN: 60396

GnomAD4 genome AF: 0.0199 AC: 3032 AN: 152332 Hom.: 109 Cov.: 33 AF XY: 0.0189 AC XY: 1406 AN XY: 74508

African (AFR) AF: 0.0684 AC: 2842 AN: 41552

American (AMR) AF: 0.00816 AC: 125 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0156 Hom.: 72

Bravo AF: 0.0224

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 08, 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.

Dec 21, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gln144Gln in exon 5 of TMPRSS3: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue is not located near a splice junction, is listed in dbSNP (rs61731564, 3 control submissions) and ha s been found in 10% of Black and/or Hispanic cases in our laboratory.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive nonsyndromic hearing loss 8 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Feb 14, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61731564; hg19: chr21-43808526;