11-121168135-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_005422.4(TECTA):c.5668C>T(p.Arg1890Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.43

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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;

PP5

Variant 11-121168135-C-T is Pathogenic according to our data. Variant chr11-121168135-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121168135-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4 link	c.5668C>T	p.Arg1890Cys	missense_variant	Exon 19 of 24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 link	c.6610C>T	p.Arg2204Cys	missense_variant	Exon 25 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6 link	c.5668C>T	p.Arg1890Cys	missense_variant	Exon 19 of 24	5	NM_005422.4	ENSP00000376543.1		O75443

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Nov 09, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1890Cys variant (rs121909063) has been shown segregating with sensorineural hearing loss across four families including Dutch, American and two Spanish (Plantinga, 2006 and Hildebrand, 2011). All affected individuals display middle frequencies impairment indicated by a trough-shaped profile in the audiogram. This variant occurs in the ZP domain of TECTA, a region of the polypeptide required for polymerization into high molecular weight filaments where it is incorporated into the extracellular matrix (Jovine, 2002). This variant is listed in the Genome Aggregation Database (gnomAD) identified on a single chromosome out of 246,248, and has been reported to the ClinVar database as a pathogenic variant (Variation ID: 7022). The arginine at position 1890 is highly conserved considering 11 species (Alamut v2.10) and computational analyses of the p.Arg1890Cys variant on protein structure and function indicate a deleterious effect (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: probably damaging). Given the current evidence, the p.Arg1890Cys is likely to be pathogenic. -

Mar 25, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18022253, 24636747, 18776598, 17136632, 28946916, 16718611, 31554319, 33297549, 27535533, 21520338, 9590290, 30935366) -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1890 of the TECTA protein (p.Arg1890Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant deafness (PMID: 16718611, 21520338, 28946916, 30935366, 31554319, 33297549, 34795337). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7022). Invitae Evidence 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 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. -

Autosomal dominant nonsyndromic hearing loss 12

Pathogenic:2

Jun 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3+PS4_Moderate+PP1_Strong -

Nonsyndromic genetic hearing loss

Pathogenic:1

Jul 15, 2021

INGEBI, INGEBI / CONICET

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.5688C>T variant in TECTA gene is absent from population databases applying to PM2 criteria. This variant has been detected in two different probands meeting PS4_ Supporing (PMID: 16718611 and this study). This change segregated in eleven affected memebers in a family and 4 affected memebrs in another family, both with non-syndromic hearing loss which meets the PP1_VeryStrong criteria (PMID: 16718611 and this study). Revel score was 0.503 not apllying neither PM3 nor BP4. Consider all the evidene (PM2, PP1_Strong and PS4_Supp) the variant is classified as Pathogenic for autosomal dominant non-syndromic hearing loss -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;.;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

.;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

0.69

N;.;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;.;N

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;.;D

Sift4G

Pathogenic

0.0010

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.85

MVP

0.92

MPC

1.1

ClinPred

0.93

GERP RS

4.3

Varity_R

0.49

gMVP

0.46

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