11-121137576-C-T

Position:

chr11-121137576-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA182517/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:7

Conservation

PhyloP100: 1.51

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:54857): (TBCEL-TECTA readthrough) Predicted to enable alpha-tubulin binding activity. Predicted to be involved in microtubule cytoskeleton organization; post-chaperonin tubulin folding pathway; and tubulin complex assembly. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TBCEL-TECTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4 link	c.3097C>T	p.Arg1033Trp	missense_variant	11/24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 link	c.4054C>T	p.Arg1352Trp	missense_variant	17/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TECTA	ENST00000392793.6 link	c.3097C>T	p.Arg1033Trp	missense_variant	11/24	5	NM_005422.4	ENSP00000376543.1	O75443
TECTA	ENST00000264037.2 link	c.3097C>T	p.Arg1033Trp	missense_variant	10/23	1		ENSP00000264037.2	O75443
TECTA	ENST00000642222.1 link	c.3097C>T	p.Arg1033Trp	missense_variant	11/24			ENSP00000493855.1	A0A2R8YDL0
TECTA	ENST00000645008.1 link	c.403C>T	p.Arg135Trp	missense_variant	2/15			ENSP00000496274.1	A0A2R8YGQ5

Frequencies

GnomAD3 genomes

AF:

0.00140

AC:

212

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000974

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251328

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000200

AC:

293

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

128

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00349

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.00140

AC:

213

AN:

152038

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00323

Gnomad4 AMR

AF:

0.00419

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000976

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000283

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	Identified in a patient with hearing loss who was also heterozygous for the Q234R variant (Sloan-Heggen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26969326) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	- -

not specified

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2018	The p.Arg1033Trp variant (rs142486386) has been reported in the medical literature in a single individual with a suspected diagnosis of non-syndromic hearing loss; however, inheritance and specific clinical information were not reported for this individual (Sloan-Heggen 2016). The p.Arg1033Trp variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.34% in the African population (identified in 81 out of 24,020 chromosomes), and is listed in the ClinVar database (Variant ID: 178538). The arginine at codon 1033 is highly conserved considering 11 species up to Tetraodon (Alamut software v2.10.0), and computational analyses suggest that this variant does affect the structure/function of the TECTA protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). While the p.Arg1033Trp variant appears to be an ethnic specific polymorphism in the African population, the available evidence is insufficient to classify this variant with certainty. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 22, 2017	p.Arg1033Trp in exon 10 of TECTA: This variant is not expected to have clinical significance because it has been identified in 0.3% (81/24020) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs142486386). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2021	Variant summary: TECTA c.3097C>T (p.Arg1033Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282672 control chromosomes, predominantly at a frequency of 0.0035 within the African or African-American subpopulation in the gnomAD database. This frequency is equal to the estimated maximal expected allele frequency of a pathogenic variant in TECTA causing Deafness, Autosomal Recessive 21 (0.0035 vs 0.0035), suggesting this may be a benign polymorphism. c.3097C>T has been reported in the literature in one individual affected with hearing loss (Sloan-Heggen_2016). The report does not provide unequivocal conclusions about association of the variant with Deafness, Autosomal Recessive 21. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=4), including one expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Nonsyndromic genetic hearing loss

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Apr 29, 2019

The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. -

TECTA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

D;.;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.2

M;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.1

N;.;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.027

D;.;D

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.85

MVP

0.92

MPC

1.0

ClinPred

0.037

GERP RS

4.3

Varity_R

0.29

gMVP

0.72

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

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