rs45598239

Positions:

• chr21-42388983-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.268G>A​(p.Ala90Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0447 in 1,614,130 control chromosomes in the GnomAD database, including 1,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (124 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1793 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.28

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037552118).
• BP6: Variant 21-42388983-C-T is Benign according to our data. Variant chr21-42388983-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42388983-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.268G>A	p.Ala90Thr	missense_variant	4/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.268G>A	p.Ala90Thr	missense_variant	4/13		NP_076927.1
TMPRSS3	NM_032405.2	c.268G>A	p.Ala90Thr	missense_variant	4/9		NP_115781.1
TMPRSS3	NM_032404.3	c.-114G>A		5_prime_UTR_variant	1/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.268G>A	p.Ala90Thr	missense_variant	4/13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4946 AN: 152208 Hom.: 124 Cov.: 33

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0318 AC: 7990 AN: 251426 Hom.: 207 AF XY: 0.0320 AC XY: 4353 AN XY: 135894

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00581

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0520

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0459 AC: 67147 AN: 1461804 Hom.: 1793 Cov.: 33 AF XY: 0.0447 AC XY: 32521 AN XY: 727196

Gnomad4 AFR exome AF: 0.00648

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00610

Gnomad4 FIN exome AF: 0.0408

Gnomad4 NFE exome AF: 0.0545

Gnomad4 OTH exome AF: 0.0380

GnomAD4 genome AF: 0.0325 AC: 4945 AN: 152326 Hom.: 124 Cov.: 33 AF XY: 0.0306 AC XY: 2283 AN XY: 74488

Gnomad4 AFR AF: 0.00765

Gnomad4 AMR AF: 0.0185

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0331

Gnomad4 NFE AF: 0.0541

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0479 Hom.: 335

Bravo AF: 0.0310

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0483 AC: 415

ExAC AF: 0.0330 AC: 4003

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0472

EpiControl AF: 0.0469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 26, 2010	Ala90Thr in exon 4 of TMPRSS3: This variant has been identified in 4/178 (2.2%) probands with hearing loss (Rehm, unpublished data; Hutchin 2005) and was absent from 165 controls. However, in all 4 probands, a second variant was not identif ied. In addition, this variant has been identified in several control studies (r s45598239 ? 4 submissions) including 2/10 controls in our laboratory. In summary , this data suggests that the variant is benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 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	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 20, 2022	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;.;D;D;D
MetaRNN	Benign	0.0038	T;T;T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	M;M;M;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	.;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.60	.;T;T;T;T
Sift4G	Benign	0.54	.;T;T;T;T
Polyphen		0.98	D;D;D;.;D
Vest4		0.24, 0.21, 0.50
MPC		0.48
ClinPred		0.038	T
GERP RS		5.2
Varity_R		0.10
gMVP		0.64

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: rs45598239; hg19: chr21-43809092;