rs2839506

Variant names:

• chr21-42395056-A-G
• rs2839506
• NM_001256317.3:c.94+268T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001256317.3(TMPRSS3):​c.94+268T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,104 control chromosomes in the GnomAD database, including 2,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.16 (2838 hom., cov: 32)
• Consequence: TMPRSS3 NM_001256317.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.433
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 21-42395056-A-G is Benign according to our data. Variant chr21-42395056-A-G is described in ClinVar as Benign. ClinVar VariationId is 1239715.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.94+268T>C		intron_variant	Intron 2 of 12	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.94+268T>C		intron_variant	Intron 2 of 12		NP_076927.1
TMPRSS3	NM_032405.2	c.94+268T>C		intron_variant	Intron 2 of 8		NP_115781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.94+268T>C		intron_variant	Intron 2 of 12		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24088 AN: 151986 Hom.: 2833 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0940

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.0656

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.139

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.159 AC: 24113 AN: 152104 Hom.: 2838 Cov.: 32 AF XY: 0.157 AC XY: 11644 AN XY: 74370

African (AFR) AF: 0.322 AC: 13335 AN: 41430

American (AMR) AF: 0.0939 AC: 1435 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 397 AN: 3470

East Asian (EAS) AF: 0.155 AC: 801 AN: 5184

South Asian (SAS) AF: 0.186 AC: 895 AN: 4816

European-Finnish (FIN) AF: 0.0656 AC: 696 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6134 AN: 67992

Other (OTH) AF: 0.141 AC: 298 AN: 2114

Alfa AF: 0.111 Hom.: 1735

Bravo AF: 0.167

Asia WGS AF: 0.183 AC: 640 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.64
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs2839506; hg19: chr21-43815165;