rs12275038

Positions:

• chr11-121146109-G-A
• chr11-121146109-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005422.4(TECTA):​c.4098G>A​(p.Thr1366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,607,516 control chromosomes in the GnomAD database, including 41,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7227 hom., cov: 33)
  • Exomes 𝑓: 0.21 (34607 hom.)
• Consequence: TECTA NM_005422.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.01

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 11-121146109-G-A is Benign according to our data. Variant chr11-121146109-G-A is described in ClinVar as [Benign]. Clinvar id is 45329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121146109-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.4098G>A	p.Thr1366=	synonymous_variant	12/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.5055G>A	p.Thr1685=	synonymous_variant	18/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.4098G>A	p.Thr1366=	synonymous_variant	12/24	5	NM_005422.4	P4

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41570 AN: 152094 Hom.: 7215 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.00461

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.188 AC: 44846 AN: 238882 Hom.: 5545 AF XY: 0.185 AC XY: 24238 AN XY: 130704

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.00248

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.212

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.207 AC: 301908 AN: 1455304 Hom.: 34607 Cov.: 33 AF XY: 0.205 AC XY: 148106 AN XY: 724178

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.117

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.205

GnomAD4 genome AF: 0.273 AC: 41616 AN: 152212 Hom.: 7227 Cov.: 33 AF XY: 0.266 AC XY: 19830 AN XY: 74416

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.00443

Gnomad4 SAS AF: 0.146

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.263

Alfa AF: 0.216 Hom.: 4261

Bravo AF: 0.280

Asia WGS AF: 0.0920 AC: 322 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.210

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Thr1366Thr in Exon 11 of TECTA: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 46.4% (1724/3716) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12275038). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 21 Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Autosomal dominant nonsyndromic hearing loss 12 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.069
DANN	Benign	0.48

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: rs12275038; hg19: chr11-121016818;