11-121137491-C-G

Position:

• chr11-121137491-C-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.3012C>G​(p.Thr1004Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,613,882 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (86 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (101 hom.)
• Consequence: TECTA NM_005422.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.77

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=-0.61).
• BP6: Variant 11-121137491-C-G is Benign according to our data. Variant chr11-121137491-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 45325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121137491-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.3012C>G	p.Thr1004Thr	synonymous_variant	11/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3969C>G	p.Thr1323Thr	synonymous_variant	17/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.3012C>G	p.Thr1004Thr	synonymous_variant	11/24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.3012C>G	p.Thr1004Thr	synonymous_variant	10/23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.3012C>G	p.Thr1004Thr	synonymous_variant	11/24			ENSP00000493855.1
TECTA	ENST00000645008.1	c.318C>G	p.Thr106Thr	synonymous_variant	2/15			ENSP00000496274.1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3046 AN: 151882 Hom.: 86 Cov.: 32

Gnomad AFR AF: 0.0689

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00924

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00538 AC: 1351 AN: 251304 Hom.: 35 AF XY: 0.00394 AC XY: 535 AN XY: 135806

Gnomad AFR exome AF: 0.0712

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00212 AC: 3096 AN: 1461882 Hom.: 101 Cov.: 32 AF XY: 0.00180 AC XY: 1312 AN XY: 727242

Gnomad4 AFR exome AF: 0.0712

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.0201 AC: 3048 AN: 152000 Hom.: 86 Cov.: 32 AF XY: 0.0194 AC XY: 1439 AN XY: 74300

Gnomad4 AFR AF: 0.0687

Gnomad4 AMR AF: 0.00923

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00608 Hom.: 7

Bravo AF: 0.0237

Asia WGS AF: 0.00462 AC: 17 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 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	Apr 30, 2012	Thr1004Thr in Exon 10 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 7.0% (261/3738) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs61291716). -

Autosomal recessive nonsyndromic hearing loss 21 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.61
CADD	Benign	3.9
DANN	Benign	0.44

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: rs61291716; hg19: chr11-121008200;