rs115489719

Variant names:

• chr21-42382048-T-C
• rs115489719
• ENST00000398397.3:c.969A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032405.2. 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.952+17A>G		intron	N/A	NP_001243246.1
	TMPRSS3	NM_032405.2		c.969A>G	p.Leu323Leu	synonymous	Exon 9 of 9	NP_115781.1
	TMPRSS3	NM_024022.4		c.952+17A>G		intron	N/A	NP_076927.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000398397.3	TSL:1	c.969A>G	p.Leu323Leu	synonymous	Exon 9 of 9	ENSP00000381434.3
	TMPRSS3	ENST00000644384.2	MANE Select	c.952+17A>G		intron	N/A	ENSP00000494414.1
	TMPRSS3	ENST00000433957.7	TSL:1	c.952+17A>G		intron	N/A	ENSP00000411013.3

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

GnomAD2 exomes AF: 0.00308 AC: 766 AN: 249058 AF XY: 0.00225

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 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

African (AFR) AF: 0.0360 AC: 1206 AN: 33478

American (AMR) AF: 0.00257 AC: 115 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 46 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000292 AC: 325 AN: 1112010

Other (OTH) AF: 0.00298 AC: 180 AN: 60396

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

African (AFR) AF: 0.0332 AC: 1380 AN: 41544

American (AMR) AF: 0.00445 AC: 68 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00472 Hom.: 12

Bravo AF: 0.0113

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0020
DANN	Benign	0.38
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs115489719; hg19: chr21-43802157;