21-42388532-C-T

Position:

chr21-42388532-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001256317.3(TMPRSS3):c.323-6G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

TMPRSS3
NM_001256317.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9991

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 0.609

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 21-42388532-C-T is Pathogenic according to our data. Variant chr21-42388532-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46113.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=5}. Variant chr21-42388532-C-T is described in Lovd as [Likely_pathogenic]. Variant chr21-42388532-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
TMPRSS3	NM_001256317.3 linkuse as main transcript	c.323-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4 linkuse as main transcript	c.323-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_076927.1
TMPRSS3	NM_032404.3 linkuse as main transcript	c.-59-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_115780.1
TMPRSS3	NM_032405.2 linkuse as main transcript	c.323-6G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_115781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2 linkuse as main transcript	c.323-6G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001256317.3	ENSP00000494414	A1	P57727-5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251262

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000423

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 14, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 01, 2022	The TMPRSS3 c.323-6G>A variant is classified as PATHOGENIC (PVS1, PS4, PM3) The TMPRSS3 c.323-6G>A variant is located in a splice acceptor region. Studies have demonstrated this variant impacts splicing, leading to a frameshift in the open reading frame (PMID:11137999) (PVS1). This variant has been reported in both a homozygous and compound heterozygous state in multiple individuals with deafness, in the literature (PMID:11137999; PMID:30622556; PMID:34868270) (PS4) (PM3). This variant is in dbSNP (rs374793617) but is rare in population databases (gnomAD 4/152118, no homozygotes). This variant has been reported in ClinVar as Pathogenic for Hearing loss by other diagnostic laboratories (Variation ID: 46113) and as damaging in the HGMD disease database for childhood onset deafness (CS010098). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	Published functional studies demonstrate a damaging effect caused by the insertion of 4 nucleotides between exons 4 and 5 and leading to a frameshift (PMID: 11137999); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 11137999, 30622556, 34868270, 21786053, 24416283, 28695016, 32747562, 31589614, 34837038) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change falls in intron 4 of the TMPRSS3 gene. It does not directly change the encoded amino acid sequence of the TMPRSS3 protein. This variant is present in population databases (rs374793617, gnomAD 0.03%). This variant has been observed in individual(s) with deafness (PMID: 11137999). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 46113). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11137999). For these reasons, this variant has been classified as Pathogenic. -

Childhood onset hearing loss

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

National Institute on Deafness and Communication Disorders, National Institutes of Health

Jul 08, 2021

PS1, PS3_moderate, PM2, PM3_strong, PP3 / Modifications from PMID: 30311386 for classification: The genetic causes of hearing loss have not yet been well characterized in the Yoruba population, and the information regarding variant MAF in this population is still limited, so we did not exclude any variant based on their "high" MAF. PP3 criteria was applied even if the REVEL score was below 0.7, if at least two of the pathogenicity prediction algorithms used predicted that the variant was damaging or likely damaging. -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2013

The 323-6G>A variant in TMPRSS3 has been reported in homozygosity in one individ ual with hearing loss (Scott 2001). It has also been identified by our laborator y in trans with another pathogenic variant in one individual with hearing loss. The variant is located in the 3' splice region and studies have shown that the 323-6G>A variant impacts splicing and leads to a frameshift (Scott 2001). Althou gh this variant has been identified in 0.02% (1/4406) of African American chromo somes from a broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS) and in 1/160 Muslim Indians controls (Scott 2001), this f requency is low enough to be consistent with a recessive carrier frequency. In s ummary, this variant meets our criteria to be classified as pathogenic. -

TMPRSS3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 30, 2024

The TMPRSS3 c.323-6G>A variant is predicted to interfere with splicing. This variant has been reported in both the homozygous and compound heterozygous states in several individuals with hearing loss, and the change segregates with the hearing loss phenotype in families (Ganapathy et al. 2014. PubMed ID: 24416283; Gao et al. 2017. PubMed ID: 28695016; Morgan et al. 2018. PubMed ID: 30622556). RNA functional studies show that this intronic change alters splicing, resulting in an early protein termination (Scott et al. 2001. PubMed ID: 11137999, alternate nomenclature IVS4-6G>A, p.Cys107fs). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Hearing impairment

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Moderate PM2_Supporting, BP4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: -2

DS_AL_spliceai

0.48

Position offset: -6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over