rs2839500

Variant names:

• chr21-42383058-T-C
• rs2839500
• NM_001256317.3:c.757A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-42383058-T-C
• chr21-42383058-T-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. 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:7
• Conservation: PhyloP100: 0.0990
• Publications: 40 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 -17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001256317.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.
• 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 VariationId is 46129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.757A>G	p.Ile253Val	missense_variant	Exon 8 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.757A>G	p.Ile253Val	missense_variant	Exon 8 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.757A>G	p.Ile253Val	missense_variant	Exon 8 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.376A>G	p.Ile126Val	missense_variant	Exon 5 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.757A>G	p.Ile253Val	missense_variant	Exon 8 of 13		NM_001256317.3	ENSP00000494414.1

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

GnomAD2 exomes AF: 0.156 AC: 39280 AN: 251026 AF XY: 0.158

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 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

African (AFR) AF: 0.296 AC: 9895 AN: 33474

American (AMR) AF: 0.135 AC: 6043 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2631 AN: 26136

East Asian (EAS) AF: 0.326 AC: 12954 AN: 39682

South Asian (SAS) AF: 0.242 AC: 20889 AN: 86250

European-Finnish (FIN) AF: 0.0910 AC: 4852 AN: 53318

Middle Eastern (MID) AF: 0.155 AC: 894 AN: 5768

European-Non Finnish (NFE) AF: 0.106 AC: 118109 AN: 1111954

Other (OTH) AF: 0.142 AC: 8595 AN: 60392

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

African (AFR) AF: 0.282 AC: 11710 AN: 41506

American (AMR) AF: 0.142 AC: 2177 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 322 AN: 3468

East Asian (EAS) AF: 0.326 AC: 1688 AN: 5176

South Asian (SAS) AF: 0.257 AC: 1236 AN: 4812

European-Finnish (FIN) AF: 0.0874 AC: 929 AN: 10628

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7175 AN: 67994

Other (OTH) AF: 0.161 AC: 340 AN: 2116

Alfa AF: 0.130 Hom.: 7055

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 16, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 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. -

-

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

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.2
DANN	Benign	0.40
DEOGEN2	Benign	0.18	.;T;T;.;.
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
PhyloP100		0.099
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.27	.;N;N;N;N
REVEL	Benign	0.073
Sift	Benign	1.0	.;T;T;T;T
Sift4G	Benign	1.0	.;T;T;T;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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2839500; hg19: chr21-43803167; COSMIC: COSV52301747; COSMIC: COSV52301747;