chr11-121130051-T-C

Variant names:

• chr11-121130051-T-C
• rs142903119
• NM_005422.4:c.2781T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005422.4(TECTA):​c.2781T>C​(p.His927His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00466 in 1,613,996 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (25 hom.)
• Consequence: TECTA NM_005422.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.290
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-121130051-T-C is Benign according to our data. Variant chr11-121130051-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178636.
• BP7: Synonymous conserved (PhyloP=-0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00389 (592/152266) while in subpopulation NFE AF = 0.00528 (359/68016). AF 95% confidence interval is 0.00483. There are 1 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.2781T>C	p.His927His	synonymous_variant	Exon 10 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.3738T>C	p.His1246His	synonymous_variant	Exon 16 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.2781T>C	p.His927His	synonymous_variant	Exon 10 of 24	5	NM_005422.4	ENSP00000376543.1
TECTA	ENST00000264037.2	c.2781T>C	p.His927His	synonymous_variant	Exon 9 of 23	1		ENSP00000264037.2
TECTA	ENST00000642222.1	c.2781T>C	p.His927His	synonymous_variant	Exon 10 of 24			ENSP00000493855.1
TECTA	ENST00000645008.1	c.87T>C	p.His29His	synonymous_variant	Exon 1 of 15			ENSP00000496274.1

Frequencies

GnomAD3 genomes AF: 0.00388 AC: 591 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000990

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00528

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00417 AC: 1048 AN: 251094 AF XY: 0.00422

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00507

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00474 AC: 6930 AN: 1461730 Hom.: 25 Cov.: 31 AF XY: 0.00461 AC XY: 3350 AN XY: 727152

African (AFR) AF: 0.000597 AC: 20 AN: 33478

American (AMR) AF: 0.000872 AC: 39 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 152 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00179 AC: 154 AN: 86234

European-Finnish (FIN) AF: 0.0131 AC: 699 AN: 53388

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00500 AC: 5555 AN: 1111932

Other (OTH) AF: 0.00512 AC: 309 AN: 60390

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152266 Hom.: 1 Cov.: 33 AF XY: 0.00383 AC XY: 285 AN XY: 74450

African (AFR) AF: 0.000987 AC: 41 AN: 41546

American (AMR) AF: 0.00111 AC: 17 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.0132 AC: 140 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00528 AC: 359 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00453 Hom.: 1

Bravo AF: 0.00286

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00367

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Apr 11, 2018

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. -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TECTA: BP4, BP7, BS2 -

Autosomal recessive nonsyndromic hearing loss 21 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His927His in Exon 09 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 0.6% (43/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs142903119). -

Autosomal dominant nonsyndromic hearing loss 12 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.36
PhyloP100		-0.29
PromoterAI		0.058	Neutral
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs142903119; hg19: chr11-121000760;