rs113747896

Variant names:

• chr21-42376613-G-A
• rs113747896
• NM_001256317.3:c.1119C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-42376613-G-A
• chr21-42376613-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6 BP7 BS1 BS2_Supporting

The NM_001256317.3(TMPRSS3):​c.1119C>T​(p.Asp373Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000698 in 1,614,052 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: TMPRSS3 NM_001256317.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -4.29
• 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: 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-42376613-G-A is Benign according to our data. Variant chr21-42376613-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46097.
• BP7: Synonymous conserved (PhyloP=-4.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00276 (421/152278) while in subpopulation AFR AF = 0.00864 (359/41550). AF 95% confidence interval is 0.0079. There are 1 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1119C>T	p.Asp373Asp	synonymous	Exon 11 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.1122C>T	p.Asp374Asp	synonymous	Exon 11 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.741C>T	p.Asp247Asp	synonymous	Exon 8 of 10	NP_115780.1	P57727-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.1119C>T	p.Asp373Asp	synonymous	Exon 11 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.1122C>T	p.Asp374Asp	synonymous	Exon 11 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.990C>T		non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152160 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00852

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 251418 AF XY: 0.00130

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00848

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000482 AC: 705 AN: 1461774 Hom.: 3 Cov.: 32 AF XY: 0.000477 AC XY: 347 AN XY: 727184

African (AFR) AF: 0.00986 AC: 330 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00300 AC: 119 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1112002

Other (OTH) AF: 0.00116 AC: 70 AN: 60390

GnomAD4 genome AF: 0.00276 AC: 421 AN: 152278 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74450

African (AFR) AF: 0.00864 AC: 359 AN: 41550

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00772 AC: 40 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00325

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 8 (1)
-	-	1	TMPRSS3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.082
DANN	Benign	0.82
PhyloP100		-4.3
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: rs113747896; hg19: chr21-43796722;