11-121102721-A-G

Variant names:

• chr11-121102721-A-G
• rs35507522
• NM_005422.4:c.56A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005422.4(TECTA):​c.56A>G​(p.Gln19Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,613,160 control chromosomes in the GnomAD database, including 624 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (270 hom., cov: 32)
  • Exomes 𝑓: 0.012 (354 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0510
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012865365).
• BP6: Variant 11-121102721-A-G is Benign according to our data. Variant chr11-121102721-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 45339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4	c.56A>G	p.Gln19Arg	missense_variant	Exon 2 of 24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.1013A>G	p.Gln338Arg	missense_variant	Exon 8 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.56A>G	p.Gln19Arg	missense_variant	Exon 2 of 24	5	NM_005422.4	ENSP00000376543.1
TBCEL-TECTA	ENST00000645041.1	c.965A>G	p.Gln322Arg	missense_variant	Exon 7 of 10			ENSP00000496315.1

Frequencies

GnomAD3 genomes AF: 0.0375 AC: 5710 AN: 152142 Hom.: 269 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.0310

GnomAD2 exomes AF: 0.0178 AC: 4474 AN: 251098 AF XY: 0.0177

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000831

Gnomad NFE exome AF: 0.00914

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0124 AC: 18135 AN: 1460900 Hom.: 354 Cov.: 30 AF XY: 0.0130 AC XY: 9474 AN XY: 726832

African (AFR) AF: 0.117 AC: 3897 AN: 33424

American (AMR) AF: 0.0110 AC: 493 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 469 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39690

South Asian (SAS) AF: 0.0300 AC: 2584 AN: 86230

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53412

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5764

European-Non Finnish (NFE) AF: 0.00840 AC: 9330 AN: 1111196

Other (OTH) AF: 0.0182 AC: 1100 AN: 60336

GnomAD4 genome AF: 0.0376 AC: 5728 AN: 152260 Hom.: 270 Cov.: 32 AF XY: 0.0365 AC XY: 2716 AN XY: 74442

African (AFR) AF: 0.109 AC: 4533 AN: 41522

American (AMR) AF: 0.0177 AC: 271 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0321 AC: 155 AN: 4824

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00891 AC: 606 AN: 68026

Other (OTH) AF: 0.0307 AC: 65 AN: 2116

Alfa AF: 0.0193 Hom.: 259

Bravo AF: 0.0427

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.102 AC: 451

ESP6500EA AF: 0.00954 AC: 82

ExAC AF: 0.0201 AC: 2439

Asia WGS AF: 0.0150 AC: 54 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 23, 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

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gln19Arg in Exon 01 of TECTA: This variant is not expected to have clinical sign ificance because it has been identified in 10.3% (386/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35507522). -

not provided Benign:3

Nov 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 21 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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

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
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.6
DANN	Benign	0.39
DEOGEN2	Benign	0.098	.;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.12	T;.;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.55	.;N;.;N
PhyloP100		0.051
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.45	.;N;.;N
REVEL	Benign	0.068
Sift	Benign	1.0	.;T;.;T
Sift4G	Benign	1.0	.;T;.;T
Polyphen		0.0	.;B;.;B
Vest4		0.057, 0.097
MPC		0.35
ClinPred		0.0028	T
GERP RS		-1.1
PromoterAI		0.020	Neutral
Varity_R		0.043
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

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: rs35507522; hg19: chr11-120973430;