NM_005422.4:c.3743C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005422.4(TECTA):c.3743C>T(p.Pro1248Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1248S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:1O:1

Conservation

PhyloP100: 2.30

Publications

13 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14338759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4 link	c.3743C>T	p.Pro1248Leu	missense_variant	Exon 12 of 24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 link	c.4700C>T	p.Pro1567Leu	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.3743C>T	p.Pro1248Leu	missense_variant	Exon 12 of 24	5	NM_005422.4	ENSP00000376543.1		O75443

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000314

AC:

AN:

251492

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000483

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000324

AC:

473

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

233

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000375

AC:

417

AN:

1112012

Other (OTH)

AF:

0.000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000296

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41552

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.000441

Hom.:

Bravo

AF:

0.000249

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TECTA: PM2:Supporting -

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27368438, 24586623, 25262649, 27068579, 30245029, 31554319, 9590290, 21520338, 34008892) -

Autosomal recessive nonsyndromic hearing loss 21

Pathogenic:1Uncertain:1

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PP2, PP3, PP4, PP5 -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal dominant nonsyndromic hearing loss 12;C1863655:Autosomal recessive nonsyndromic hearing loss 21

Uncertain:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 12-29-2021 by Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Apr 07, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in 1 proband with HL, at most 1 segregation. -

Hearing impairment

Uncertain:1

Apr 12, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS1_Supporting, PM2_Supporting -

TECTA-related disorder

Uncertain:1

Jun 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TECTA c.3743C>T variant is predicted to result in the amino acid substitution p.Pro1248Leu. This variant has been reported in individuals with non-syndromic autosomal dominant hearing loss (Table 1, Hildebrand et al. 2011. PubMed ID: 21520338; Shearer et al. 2014. PubMed ID: 25262649; Table S1, Sommen et al. 2016. PubMed ID: 27068579; Table 1, Marinakis et al. 2021. PubMed ID: 34008892). In ClinVar, this variant has conflicting interpretations ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/403527; Table S3, Azaiez et al. 2018. PubMed ID: 30245029). It has also been interpreted as benign based on population frequency in another variant interpretation study (Table S4, Shearer et al. 2014. PubMed ID: 25262649). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.08% of alleles in Ashkenazi Jewish descendants, including 1 homozygote and a total of 518 alleles globally. This population data is not consistent with this variant being a primary cause of autosomal dominant disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant nonsyndromic hearing loss 12

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;T

Eigen

Benign

0.076

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

M;.;M

PhyloP100

2.3

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.1

D;.;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.020

D;.;D

Sift4G

Benign

0.093

T;.;T

Polyphen

0.17

B;.;B

Vest4

0.30

MVP

0.75

MPC

0.43

ClinPred

0.61

GERP RS

5.8

Varity_R

0.36

gMVP

0.72

Mutation Taster

=51/49

polymorphism

(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