chr11-121168064-C-T

Position:

chr11-121168064-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_005422.4(TECTA):c.5597C>T(p.Thr1866Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 7.54

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:

TECTA (HGNC:):

TECTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain ZP (size 254) in uniprot entity TECTA_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_005422.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

PP5

Variant 11-121168064-C-T is Pathogenic according to our data. Variant chr11-121168064-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121168064-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-121168064-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4 linkuse as main transcript	c.5597C>T	p.Thr1866Met	missense_variant	19/24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 linkuse as main transcript	c.6539C>T	p.Thr2180Met	missense_variant	25/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6 linkuse as main transcript	c.5597C>T	p.Thr1866Met	missense_variant	19/24	5	NM_005422.4	ENSP00000376543.1		O75443

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251472

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727236

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1866 of the TECTA protein (p.Thr1866Met). This variant is present in population databases (rs140236996, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 20947814, 31163360, 31554319, 32853555). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236058). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TECTA protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24006325, 18022253, 22718023, 25413827, 21917145, 21520338, 23891399, 18797289, 17431902, 12746400, 9590290, 9150164, 30935366, 31163360, 32853555, 28000701, 24586623, 31554319, 27627659, 34795337, 34599366, 20947814, 36555390, Miyanohara2024[article], 38224868, 16718611) -

Autosomal dominant nonsyndromic hearing loss 12

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 16, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP1_P,PP3. -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Feb 19, 2016	Congenital, progressive, moderate-profound HL -
Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The TECTA c.5597C>T (p.Thr1866Met) missense variant has been reported in four studies in which it is found in a total of 22 patients with hearing loss including in three in a homozygous state, in 15 in a heterozygous state and in four patients from the same family in a heterozygous state with another missense variant in cis as part of a complex allele (Sagong et al. 2010; Hildebrand et al. 2011; Brownstein et al. 2011; Moteki et al. 2012). The p.Thr1866Met variant is thought to be the causative variant from the complex allele. The p.Thr1866Met variant showed segregation with disease in a large Korean family, a large Spanish family and a Jewish family (Sagong et al. 2010; Hildebrand et al. 2011; Brownstein et al. 2011). The three individuals in whom the variant was detected in a homozygous state showed a more severe hearing loss than that of their older relatives carrying the variant in a heterozygous state (Hildebrand et al. 2011). The p.Thr1866Met variant was absent from a total of 594 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on one allele in an area of good sequence coverage so the variant is presumed to be rare. The p.Thr1866Met variant is located in the ZP domain of tectorin, which is highly conserved across species; the Thr1866 residue itself is highly conserved. Based on the collective evidence, the p.Thr1866Met variant is classified as pathogenic for autosomal dominant nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The TECTA c.5597C>T (p.T1866M) variant has been previously reported in at least 3 families with autosomal dominant nonsyndromic hearing loss. This variant affects a well-conserved amino acid located in the ZP domain of the encoded protein (PMID: 20947814; 21520338; 22718023). -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000236058, PS1_S). The variant was co-segregated with Deafness, autosomal dominant 8/12 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 21520338, 21917145) (PP1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.761, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2016

- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Sep 15, 2022

ACMG categories: PS5,PM2,PP3,PP5 -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2018

The p.Thr1866Met variant in TECTA has been reported in 6 individuals with hearin g loss and segregated in >10 affected family members (Brownstein 2011, Hildebran d 2011, Mori 2016, Moteki 2012, Sagong 2010, Su 2014, Zazo Seco 2017). In one f amily, several affected individuals were homozygous for the variant and were rep orted to have a more severe hearing loss than the heterozygotes (Hildebrand 2011 ). This variant has also been reported in ClinVar as Pathogenic/Likely Pathogen ic by four other clinical laboratories (Variation ID# 236058). It has been iden tified in 1/111688 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org; dbSNP rs140236996). Please note that for d iseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population . Computational prediction tools and conservation analysis suggest that the p.Th r1866Met variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is like ly pathogenic. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;.;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Uncertain

2.5

M;.;M

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.7

N;.;N

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0020

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.83

MVP

0.96

MPC

1.1

ClinPred

1.0

GERP RS

6.0

Varity_R

0.77

gMVP

0.74

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