rs199638531

Positions:

chr11-121146096-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2_SupportingPVS1PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.4085G>A (p.Trp1362Ter) nonsense variant in TECTA is predicted to cause a premature stop codon in biologically-relevant exon 11 of 23 total exons, leading to a truncated or absent protein in a gene in which loss of function is an established mechanism of autosomal recessive nonsyndromic hearing loss (PVS1; PMID:30192042). This variant is present in 0.01121% (14/124864) of non-Finnish European chromosomes in gnomAD v2 (PM2_Supporting). It has been observed in at least two probands presenting with nonsyndromic hearing loss (PMID:31163360; LMM internal data SCV000711208.2). One individual harbored another nonsense variant in TECTA, which was suspected to be pathogenic (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6327349/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

TECTA
NM_005422.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5U:2

Conservation

PhyloP100: 10.0

Variant links:

Genes affected

TECTA (HGNC:11720): (tectorin alpha) The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major noncollagenous components of the tectorial membrane. Mutations in the TECTA gene have been shown to be responsible for autosomal dominant nonsyndromic hearing impairment and a recessive form of sensorineural pre-lingual non-syndromic deafness. [provided by RefSeq, Jul 2008]

TECTA links:

TBCEL-TECTA (HGNC:):

TBCEL-TECTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

PM2

PM3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4 linkuse as main transcript	c.4085G>A	p.Trp1362Ter	stop_gained	12/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1 linkuse as main transcript	c.5042G>A	p.Trp1681Ter	stop_gained	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6 linkuse as main transcript	c.4085G>A	p.Trp1362Ter	stop_gained	12/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000413

AC:

AN:

242020

Hom.:

AF XY:

0.0000378

AC XY:

AN XY:

132126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000187

AC:

272

AN:

1457934

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

725424

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000243

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Trp1362*) in the TECTA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TECTA are known to be pathogenic (PMID: 11087000, 12746400, 17431902, 24130743). This variant is present in population databases (rs199638531, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 31163360). ClinVar contains an entry for this variant (Variation ID: 498538). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31163360) -

Nonsyndromic genetic hearing loss

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jan 21, 2020

The c.4085G>A (p.Trp1362Ter) nonsense variant in TECTA is predicted to cause a premature stop codon in biologically-relevant exon 11 of 23 total exons, leading to a truncated or absent protein in a gene in which loss of function is an established mechanism of autosomal recessive nonsyndromic hearing loss (PVS1; PMID: 30192042). This variant is present in 0.01121% (14/124864) of non-Finnish European chromosomes in gnomAD v2 (PM2_Supporting). It has been observed in at least two probands presenting with nonsyndromic hearing loss (PMID: 31163360; LMM internal data SCV000711208.2). One individual harbored another nonsense variant in TECTA, which was suspected to be pathogenic (PM3_Supporting). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting. -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2018

The p.Trp1362X variant in TECTA has been identified in the heterozygous state in 1 family with hearing loss; however, this family also harbored pathogenic varia nts in different genes that may explain their hearing loss (LMM data). The p.Trp 1362X variant has also been identified in 0.01% (14/124864) of European chromoso mes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVa r (Variation ID 498538). Although this variant has been seen in the general popu lation, its frequency is low enough to be consistent with a recessive carrier fr equency. This nonsense variant leads to a premature termination codon at positio n 1362, which is predicted to lead to a truncated or absent protein. Loss of fun ction of the TECTA gene is an established disease mechanism in autosomal recessi ve hearing loss (Hildebrand 2011). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PVS1, PM2_Supporting. Please note that some truncating variant s in TECTA have been reported to segregate in an autosomal dominant manner (Coli n 2008, Hildebrand 2011); however, there is currently insufficient data to predi ct whether the p.Trp1362X variant can lead to dominantly inherited hearing loss. -

Autosomal recessive nonsyndromic hearing loss 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The TECTA c.4085G>A (p.Trp1362Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for a recessive form of nonsyndromic hearing loss. -

Autosomal dominant nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

A;A

Vest4

0.95

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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