rs2839501

Variant names:

• chr21-42385528-C-T
• rs2839501
• NM_001256317.3:c.453G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-42385528-C-T
• chr21-42385528-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256317.3(TMPRSS3):​c.453G>A​(p.Val151Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,612,724 control chromosomes in the GnomAD database, including 121,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20835 hom., cov: 32)
  • Exomes 𝑓: 0.36 (100230 hom.)
• Consequence: TMPRSS3 NM_001256317.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.09
• Publications: 33 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 21-42385528-C-T is Benign according to our data. Variant chr21-42385528-C-T is described in ClinVar as Benign. ClinVar VariationId is 46122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.804 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	NM_001256317.3	MANE Select	c.453G>A	p.Val151Val	synonymous	Exon 6 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.453G>A	p.Val151Val	synonymous	Exon 6 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.453G>A	p.Val151Val	synonymous	Exon 6 of 9	NP_115781.1	P57727-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.453G>A	p.Val151Val	synonymous	Exon 6 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.453G>A	p.Val151Val	synonymous	Exon 6 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.453G>A	p.Val151Val	synonymous	Exon 6 of 9	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.478 AC: 72603 AN: 151956 Hom.: 20783 Cov.: 32

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.360 AC: 90420 AN: 251436 AF XY: 0.352

Gnomad AFR exome AF: 0.823

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.267

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.362 AC: 528370 AN: 1460650 Hom.: 100230 Cov.: 44 AF XY: 0.359 AC XY: 260652 AN XY: 726732

African (AFR) AF: 0.829 AC: 27733 AN: 33458

American (AMR) AF: 0.312 AC: 13953 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9690 AN: 26128

East Asian (EAS) AF: 0.274 AC: 10862 AN: 39672

South Asian (SAS) AF: 0.300 AC: 25833 AN: 86228

European-Finnish (FIN) AF: 0.285 AC: 15210 AN: 53380

Middle Eastern (MID) AF: 0.409 AC: 2356 AN: 5766

European-Non Finnish (NFE) AF: 0.359 AC: 399356 AN: 1110946

Other (OTH) AF: 0.387 AC: 23377 AN: 60350

GnomAD4 genome AF: 0.478 AC: 72716 AN: 152074 Hom.: 20835 Cov.: 32 AF XY: 0.469 AC XY: 34850 AN XY: 74314

African (AFR) AF: 0.811 AC: 33649 AN: 41496

American (AMR) AF: 0.412 AC: 6301 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1318 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1446 AN: 5152

South Asian (SAS) AF: 0.283 AC: 1362 AN: 4816

European-Finnish (FIN) AF: 0.280 AC: 2956 AN: 10574

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.357 AC: 24255 AN: 67954

Other (OTH) AF: 0.478 AC: 1007 AN: 2106

Alfa AF: 0.401 Hom.: 20639

Bravo AF: 0.500

Asia WGS AF: 0.356 AC: 1241 AN: 3478

EpiCase AF: 0.359

EpiControl AF: 0.366

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal recessive nonsyndromic hearing loss 8 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.19
DANN	Benign	0.54
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2839501; hg19: chr21-43805637; COSMIC: COSV52302894; COSMIC: COSV52302894;