rs115489719

Positions:

• chr21-42382048-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032405.2(TMPRSS3):​c.969A>G​(p.Leu323Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,164 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (17 hom.)
• Consequence: TMPRSS3 NM_032405.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.73

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 21-42382048-T-C is Benign according to our data. Variant chr21-42382048-T-C is described in ClinVar as [Benign]. Clinvar id is 46133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0098 (1492/152276) while in subpopulation AFR AF= 0.0332 (1380/41544). AF 95% confidence interval is 0.0318. There are 25 homozygotes in gnomad4. There are 696 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.952+17A>G		intron_variant		ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_032405.2	c.969A>G	p.Leu323Leu	synonymous_variant	9/9		NP_115781.1
TMPRSS3	NM_024022.4	c.952+17A>G		intron_variant			NP_076927.1
TMPRSS3	NM_032404.3	c.571+17A>G		intron_variant			NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.952+17A>G		intron_variant			NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1485 AN: 152158 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00308 AC: 766 AN: 249058 Hom.: 13 AF XY: 0.00225 AC XY: 303 AN XY: 134822

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00129 AC: 1888 AN: 1461888 Hom.: 17 Cov.: 31 AF XY: 0.00115 AC XY: 834 AN XY: 727246

Gnomad4 AFR exome AF: 0.0360

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00980 AC: 1492 AN: 152276 Hom.: 25 Cov.: 32 AF XY: 0.00935 AC XY: 696 AN XY: 74460

Gnomad4 AFR AF: 0.0332

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00481 Hom.: 11

Bravo AF: 0.0113

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	May 07, 2012	Leu323Leu in Exon 09 of TMPRSS3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 3.4% (126/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs115489719). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2025	- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs115489719; hg19: chr21-43802157;