11-121125583-A-G

Variant names:

• chr11-121125583-A-G
• rs536069
• NM_005422.4:c.1485A>G

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.1485A>G​(p.Ala495Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.708 in 1,613,962 control chromosomes in the GnomAD database, including 407,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44421 hom., cov: 33)
  • Exomes 𝑓: 0.70 (363002 hom.)
• Consequence: TECTA NM_005422.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -9.07

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: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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-121125583-A-G is Benign according to our data. Variant chr11-121125583-A-G is described in ClinVar as [Benign]. Clinvar id is 45315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121125583-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-9.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.1485A>G	p.Ala495Ala	synonymous_variant	Exon 8 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.2442A>G	p.Ala814Ala	synonymous_variant	Exon 14 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.1485A>G	p.Ala495Ala	synonymous_variant	Exon 8 of 24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.1485A>G	p.Ala495Ala	synonymous_variant	Exon 7 of 23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.1485A>G	p.Ala495Ala	synonymous_variant	Exon 8 of 24			ENSP00000493855.1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114975 AN: 152124 Hom.: 44364 Cov.: 33

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.624

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.734

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.692

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.703 AC: 176656 AN: 251170 Hom.: 62926 AF XY: 0.704 AC XY: 95561 AN XY: 135766

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.674

Gnomad SAS exome AF: 0.724

Gnomad FIN exome AF: 0.729

Gnomad NFE exome AF: 0.697

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.703 AC: 1027389 AN: 1461720 Hom.: 363002 Cov.: 97 AF XY: 0.704 AC XY: 511674 AN XY: 727158

Gnomad4 AFR exome AF: 0.942

Gnomad4 AMR exome AF: 0.623

Gnomad4 ASJ exome AF: 0.622

Gnomad4 EAS exome AF: 0.682

Gnomad4 SAS exome AF: 0.721

Gnomad4 FIN exome AF: 0.736

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.756 AC: 115079 AN: 152242 Hom.: 44421 Cov.: 33 AF XY: 0.755 AC XY: 56178 AN XY: 74424

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.611

Gnomad4 EAS AF: 0.674

Gnomad4 SAS AF: 0.734

Gnomad4 FIN AF: 0.724

Gnomad4 NFE AF: 0.692

Gnomad4 OTH AF: 0.742

Alfa AF: 0.703 Hom.: 21777

Bravo AF: 0.757

Asia WGS AF: 0.725 AC: 2522 AN: 3478

EpiCase AF: 0.689

EpiControl AF: 0.690

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala495Ala in Exon 07 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 31.0% (2176/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs536069). -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 21 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 12 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.034
DANN	Benign	0.22

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: rs536069; hg19: chr11-120996292; COSMIC: COSV50687976; COSMIC: COSV50687976;