NM_005422.4:c.4004G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.4004G>A variant in TECTA is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 1335. The filtering allele frequency of this variant in gnomAD v4.1 is 0.2865% in the African/African American population, and there was agreement to apply BS1, which has a threshold of 0.3% for the ClinGen Hearing Loss group. The computational predictor REVEL gives a score of 0.35, which is neither above nor below the thresholds predicting a damaging or benign impact on TECTA function (BP4 and PP3 not met). The variant has been detected in heterozygosity in 1 individual with sloping moderately-severe sensorineural hearing loss, but no variant on the other allele was identified (Partners LMM internal data, SCV000711207.2). This variant has been observed in the heterozygous state and in combination with a second variant (phase unknown) in individuals undergoing testing for hearing loss (GeneDx internal data, SCV001770060.3). The variant has also been detected with another TECTA variant of uncertain significance in phase unknown in a patient with bilateral sensorineural hearing loss, and in the homozygous state in a patient with sensorineural hearing loss (Labcorp internal data, SCV001051355.5). In summary, this variant meets criteria to be classified as likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6327326/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 5.22

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4 link	c.4004G>A	p.Gly1335Glu	missense_variant	Exon 12 of 24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 link	c.4961G>A	p.Gly1654Glu	missense_variant	Exon 18 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6 link	c.4004G>A	p.Gly1335Glu	missense_variant	Exon 12 of 24	5	NM_005422.4	ENSP00000376543.1		O75443

Frequencies

GnomAD3 genomes

AF:

0.00100

AC:

153

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000243

AC:

AN:

250702

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00329

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461740

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00302

AC:

101

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112008

Other (OTH)

AF:

0.000215

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00100

AC:

153

AN:

152360

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00334

AC:

139

AN:

41588

American (AMR)

AF:

0.000719

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000629

Hom.:

Bravo

AF:

0.00130

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 19, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:1

Sep 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly1335Glu in exon 11 of TECTA: This variant is not expected to have clinical significance because it has been identified in 0.3% (38/10052) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148619105). -

Nonsyndromic genetic hearing loss

Benign:1

May 21, 2025

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.4004G>A variant in TECTA is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 1335. The filtering allele frequency of this variant in gnomAD v4.1 is 0.2865% in the African/African American population, and there was agreement to apply BS1, which has a threshold of 0.3% for the ClinGen Hearing Loss group. The computational predictor REVEL gives a score of 0.35, which is neither above nor below the thresholds predicting a damaging or benign impact on TECTA function (BP4 and PP3 not met). The variant has been detected in heterozygosity in 1 individual with sloping moderately-severe sensorineural hearing loss, but no variant on the other allele was identified (Partners LMM internal data, SCV000711207.2). This variant has been observed in the heterozygous state and in combination with a second variant (phase unknown) in individuals undergoing testing for hearing loss (GeneDx internal data, SCV001770060.3). The variant has also been detected with another TECTA variant of uncertain significance in phase unknown in a patient with bilateral sensorineural hearing loss, and in the homozygous state in a patient with sensorineural hearing loss (Labcorp internal data, SCV001051355.5). In summary, this variant meets criteria to be classified as likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: BS1 (ClinGen Hearing Loss VCEP specifications version 2; 5/21/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.051

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.2

L;.;L

PhyloP100

5.2

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

D;.;D

REVEL

Uncertain

0.35

Sift

Benign

0.037

D;.;D

Sift4G

Benign

0.36

T;.;T

Polyphen

0.70

P;.;P

Vest4

0.32

MVP

0.90

MPC

0.85

ClinPred

0.049

GERP RS

5.0

Varity_R

0.38

gMVP

0.64

Mutation Taster

=47/53

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over