rs2839500

chr21-42383058-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):c.757A>G(p.Ile253Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,874 control chromosomes in the GnomAD database, including 16,820 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I253T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2742 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14078 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0990

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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001256317.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.004363686).
• BP6: Variant 21-42383058-T-C is Benign according to our data. Variant chr21-42383058-T-C is described in ClinVar as [Benign]. Clinvar id is 46129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42383058-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.757A>G	p.Ile253Val	missense_variant	8/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.757A>G	p.Ile253Val	missense_variant	8/13
TMPRSS3	NM_032405.2	c.757A>G	p.Ile253Val	missense_variant	8/9
TMPRSS3	NM_032404.3	c.376A>G	p.Ile126Val	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.757A>G	p.Ile253Val	missense_variant	8/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25634 AN: 152080 Hom.: 2734 Cov.: 33

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.156 AC: 39280 AN: 251026 Hom.: 3865 AF XY: 0.158 AC XY: 21420 AN XY: 135714

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.329

Gnomad SAS exome AF: 0.250

Gnomad FIN exome AF: 0.0880

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.126 AC: 184862 AN: 1461674 Hom.: 14078 Cov.: 32 AF XY: 0.129 AC XY: 93978 AN XY: 727142

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.0910

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.169 AC: 25680 AN: 152200 Hom.: 2742 Cov.: 33 AF XY: 0.170 AC XY: 12627 AN XY: 74422

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.0928

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.0874

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.161

Alfa AF: 0.124 Hom.: 3530

Bravo AF: 0.177

TwinsUK AF: 0.114 AC: 422

ALSPAC AF: 0.105 AC: 404

ESP6500AA AF: 0.271 AC: 1196

ESP6500EA AF: 0.103 AC: 887

ExAC AF: 0.163 AC: 19733

Asia WGS AF: 0.294 AC: 1025 AN: 3478

EpiCase AF: 0.111

EpiControl AF: 0.109

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 16, 2007	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:2

Benign, 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 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	5.2
Dann	Benign	0.40
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.46	T;.;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.46	N;N;N;.;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.43	T
Polyphen		0.0	B;B;B;.;B
Vest4		0.043, 0.040, 0.11
MPC		0.088
ClinPred		0.00040	T
GERP RS		4.6
Varity_R		0.040
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2839500; hg19: chr21-43803167; COSMIC: COSV52301747; COSMIC: COSV52301747;