rs147890616

Positions:

chr11-121137885-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005422.4(TECTA):c.3406G>C(p.Asp1136His) variant causes a missense change. The variant allele was found at a frequency of 0.000103 in 1,602,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.85

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.061835825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4 linkuse as main transcript	c.3406G>C	p.Asp1136His	missense_variant	11/24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 linkuse as main transcript	c.4363G>C	p.Asp1455His	missense_variant	17/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TECTA	ENST00000392793.6 linkuse as main transcript	c.3406G>C	p.Asp1136His	missense_variant	11/24	5	NM_005422.4	ENSP00000376543.1	O75443
TECTA	ENST00000264037.2 linkuse as main transcript	c.3406G>C	p.Asp1136His	missense_variant	10/23	1		ENSP00000264037.2	O75443
TECTA	ENST00000642222.1 linkuse as main transcript	c.3406G>C	p.Asp1136His	missense_variant	11/24			ENSP00000493855.1	A0A2R8YDL0
TECTA	ENST00000645008.1 linkuse as main transcript	c.712G>C	p.Asp238His	missense_variant	2/15			ENSP00000496274.1	A0A2R8YGQ5

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000149

AC:

AN:

248382

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

133988

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000348

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:

0.0000802

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000848

AC:

123

AN:

1450734

Hom.:

Cov.:

AF XY:

0.0000654

AC XY:

AN XY:

719186

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000404

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:

0.0000480

Gnomad4 OTH exome

AF:

0.000167

GnomAD4 genome

AF:

0.000276

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000491

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	Reported in association with autosomal dominant hearing loss in published literature (PMID: 21520338); In silico analysis indicates that this missense variant does not alter protein structure/function; Located in the von Willebrand factor type D3 subdomain of the zonadhesin domain (PMID: 21520338, 31554319, 9590290); This variant is associated with the following publications: (PMID: 25262649, 30245029, 27368438, 21520338, 31554319, 9590290) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 06, 2013

The Asp1136His variant in TECTA has been reported in a Spanish family with domin ant postlingual mid-frequency hearing loss (Hildebrand 2011); however, the autho rs did not report the number of family members who were tested and whether the v ariant co-segregated in all affected members. This variant has also been identif ied in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequenc ing Project and in 1/100 (1%) Puerto Rican chromosomes by the 1000 Genomes Proje ct (http://evs.gs.washington.edu/EVS/; dbSNP rs147890616). Although, this varian t has been reported in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. In summary, additional informatio n is needed to fully assess the clinical significance of this variant. -

Autosomal recessive nonsyndromic hearing loss 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Autosomal dominant nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.062

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.1

M;.;M

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.20

Sift

Uncertain

0.0090

D;.;D

Sift4G

Uncertain

0.047

D;.;D

Polyphen

0.87

P;.;P

Vest4

0.37

MVP

0.77

MPC

0.39

ClinPred

0.051

GERP RS

3.7

Varity_R

0.21

gMVP

0.59

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