11-121128233-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005422.4(TECTA):c.2256C>T(p.Ile752=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,601,288 control chromosomes in the GnomAD database, including 68,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5753 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62686 hom.)
• Consequence: TECTA NM_005422.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.546

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 11-121128233-C-T is Benign according to our data. Variant chr11-121128233-C-T is described in ClinVar as [Benign]. Clinvar id is 45319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121128233-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.546 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.2256C>T	p.Ile752=	synonymous_variant	9/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.3213C>T	p.Ile1071=	synonymous_variant	15/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.2256C>T	p.Ile752=	synonymous_variant	9/24	5	NM_005422.4	P4
TECTA	ENST00000264037.2	c.2256C>T	p.Ile752=	synonymous_variant	8/23	1		P4
TECTA	ENST00000642222.1	c.2256C>T	p.Ile752=	synonymous_variant	9/24			A1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40605 AN: 151984 Hom.: 5752 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.301

GnomAD3 exomes AF: 0.307 AC: 74163 AN: 241670 Hom.: 12124 AF XY: 0.315 AC XY: 41410 AN XY: 131340

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.408

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.290 AC: 420029 AN: 1449186 Hom.: 62686 Cov.: 67 AF XY: 0.295 AC XY: 212889 AN XY: 721308

Gnomad4 AFR exome AF: 0.184

Gnomad4 AMR exome AF: 0.282

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.280

Gnomad4 OTH exome AF: 0.304

GnomAD4 genome AF: 0.267 AC: 40630 AN: 152102 Hom.: 5753 Cov.: 32 AF XY: 0.273 AC XY: 20299 AN XY: 74332

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.301

Alfa AF: 0.283 Hom.: 8894

Bravo AF: 0.262

Asia WGS AF: 0.424 AC: 1474 AN: 3478

EpiCase AF: 0.300

EpiControl AF: 0.304

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ile752Ile in Exon 08 of TECTA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 28.8% (2021/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10502247). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 21 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Autosomal dominant nonsyndromic hearing loss 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	4.3
Dann	Benign	0.81

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: rs10502247; hg19: chr11-120998942; COSMIC: COSV50767501; COSMIC: COSV50767501;