rs928302

chr21-42389975-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):c.157G>A(p.Val53Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0762 in 1,613,530 control chromosomes in the GnomAD database, including 5,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (595 hom., cov: 33)
  • Exomes 𝑓: 0.075 (5058 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013293326).
• BP6: Variant 21-42389975-C-T is Benign according to our data. Variant chr21-42389975-C-T is described in ClinVar as [Benign]. Clinvar id is 46105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42389975-C-T is described in Lovd as [Benign]. Variant chr21-42389975-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.157G>A	p.Val53Ile	missense_variant	3/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.157G>A	p.Val53Ile	missense_variant	3/13
TMPRSS3	NM_032405.2	c.157G>A	p.Val53Ile	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.157G>A	p.Val53Ile	missense_variant	3/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12783 AN: 152086 Hom.: 597 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0766

GnomAD3 exomes AF: 0.0756 AC: 19019 AN: 251458 Hom.: 969 AF XY: 0.0704 AC XY: 9567 AN XY: 135906

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.192

Gnomad SAS exome AF: 0.0284

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0754 AC: 110158 AN: 1461326 Hom.: 5058 Cov.: 31 AF XY: 0.0730 AC XY: 53084 AN XY: 726984

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0206

Gnomad4 EAS exome AF: 0.239

Gnomad4 SAS exome AF: 0.0295

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0735

Gnomad4 OTH exome AF: 0.0726

GnomAD4 genome AF: 0.0840 AC: 12781 AN: 152204 Hom.: 595 Cov.: 33 AF XY: 0.0825 AC XY: 6142 AN XY: 74420

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0957

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.207

Gnomad4 SAS AF: 0.0344

Gnomad4 FIN AF: 0.0578

Gnomad4 NFE AF: 0.0689

Gnomad4 OTH AF: 0.0758

Alfa AF: 0.0705 Hom.: 1121

Bravo AF: 0.0884

TwinsUK AF: 0.0742 AC: 275

ALSPAC AF: 0.0729 AC: 281

ESP6500AA AF: 0.110 AC: 484

ESP6500EA AF: 0.0658 AC: 566

ExAC AF: 0.0732 AC: 8886

Asia WGS AF: 0.100 AC: 349 AN: 3478

EpiCase AF: 0.0648

EpiControl AF: 0.0642

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.96
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.64	T;.;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N;.;N
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.49	T
Polyphen		0.035	B;B;B;.;B
Vest4		0.030, 0.028, 0.022, 0.074
MPC		0.090
ClinPred		0.0028	T
GERP RS		4.2
Varity_R		0.033
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs928302; hg19: chr21-43810084; COSMIC: COSV52301142; COSMIC: COSV52301142;