rs186972955

chr21-42375728-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001256317.3(TMPRSS3):c.1332C>T(p.His444=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000634 in 1,613,728 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00062 (2 hom.)
• Consequence: TMPRSS3 NM_001256317.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.373

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 21-42375728-G-A is Benign according to our data. Variant chr21-42375728-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178547.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=3}.
• BP7: Synonymous conserved (PhyloP=-0.373 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000742 (113/152230) while in subpopulation EAS AF= 0.0143 (74/5160). AF 95% confidence interval is 0.0117. There are 1 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.1332C>T	p.His444=	synonymous_variant	12/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.1335C>T	p.His445=	synonymous_variant	12/13
TMPRSS3	NM_032404.3	c.954C>T	p.His318=	synonymous_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1332C>T	p.His444=	synonymous_variant	12/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152112 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00129 AC: 324 AN: 251382 Hom.: 2 AF XY: 0.00121 AC XY: 164 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0153

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000623 AC: 910 AN: 1461498 Hom.: 2 Cov.: 32 AF XY: 0.000594 AC XY: 432 AN XY: 727072

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00751

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.0000943

Gnomad4 NFE exome AF: 0.000442

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152230 Hom.: 1 Cov.: 31 AF XY: 0.000900 AC XY: 67 AN XY: 74438

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.000805

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 8 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 05, 2015

p.His445His in exon 12 of TMPRSS3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 1.5% (126/8644) o f East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs186972955 -

TMPRSS3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	1.9
Dann	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs186972955; hg19: chr21-43795837;