11-121168135-C-T

Position:

• chr11-121168135-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.43

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]

TBCEL-TECTA (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.5668C>T	p.Arg1890Cys	missense_variant	19/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.6610C>T	p.Arg2204Cys	missense_variant	25/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.5668C>T	p.Arg1890Cys	missense_variant	19/24	5	NM_005422.4	ENSP00000376543	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 01, 2023	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). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2017	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. -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Jul 15, 2021

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 -

Autosomal dominant nonsyndromic hearing loss 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;.;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.69	N;.;N
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.75	T
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	D
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

Other links and lift over

dbSNP: rs121909063; hg19: chr11-121038844; COSMIC: COSV50700147;