rs56283966

chr21-42383199-C-CTAchr21-42383199-CTA-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):c.617-2_617-1insTA variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0958 in 1,613,862 control chromosomes in the GnomAD database, including 9,652 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1028 hom., cov: 31)
  • Exomes 𝑓: 0.095 (8624 hom.)
• Consequence: TMPRSS3 NM_001256317.3 splice_acceptor
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.11

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 -12 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.121145375 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of 0 (no position change), new splice context is: ctttgttcccctccatatAGcct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 21-42383199-C-CTA is Benign according to our data. Variant chr21-42383199-C-CTA is described in ClinVar as [Likely_benign]. Clinvar id is 46126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.617-2_617-1insTA		splice_acceptor_variant		ENST00000644384.2
TMPRSS3	NM_024022.4	c.617-2_617-1insTA		splice_acceptor_variant
TMPRSS3	NM_032404.3	c.236-2_236-1insTA		splice_acceptor_variant
TMPRSS3	NM_032405.2	c.617-2_617-1insTA		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.617-2_617-1insTA		splice_acceptor_variant			NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15793 AN: 152132 Hom.: 1030 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0945

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0771

Gnomad OTH AF: 0.0999

GnomAD3 exomes AF: 0.120 AC: 30217 AN: 250988 Hom.: 2471 AF XY: 0.123 AC XY: 16706 AN XY: 135694

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0868

Gnomad EAS exome AF: 0.309

Gnomad SAS exome AF: 0.220

Gnomad FIN exome AF: 0.0778

Gnomad NFE exome AF: 0.0784

Gnomad OTH exome AF: 0.0951

GnomAD4 exome AF: 0.0950 AC: 138825 AN: 1461612 Hom.: 8624 Cov.: 32 AF XY: 0.0982 AC XY: 71386 AN XY: 727102

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.0856

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.0803

Gnomad4 NFE exome AF: 0.0770

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.104 AC: 15815 AN: 152250 Hom.: 1028 Cov.: 31 AF XY: 0.107 AC XY: 7929 AN XY: 74434

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0942

Gnomad4 ASJ AF: 0.0769

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0771

Gnomad4 OTH AF: 0.0998

Alfa AF: 0.0853 Hom.: 119

Bravo AF: 0.106

Asia WGS AF: 0.265 AC: 920 AN: 3478

EpiCase AF: 0.0802

EpiControl AF: 0.0779

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Feb 16, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Nonsyndromic Hearing Loss, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34966432; hg19: chr21-43803308;