rs35507522

chr11-121102721-A-G

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:7
• Conservation: PhyloP100: 0.0510

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 -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. Variant chr11-121102721-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
TECTA	NM_005422.4	c.56A>G	p.Gln19Arg	missense_variant	2/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.1013A>G	p.Gln338Arg	missense_variant	8/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.56A>G	p.Gln19Arg	missense_variant	2/24	5	NM_005422.4	P4
TECTA	ENST00000264037.2	c.56A>G	p.Gln19Arg	missense_variant	1/23	1		P4
TECTA	ENST00000642222.1	c.56A>G	p.Gln19Arg	missense_variant	2/24			A1

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

GnomAD3 exomes AF: 0.0178 AC: 4474 AN: 251098 Hom.: 142 AF XY: 0.0177 AC XY: 2408 AN XY: 135684

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 SAS exome AF: 0.0301

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

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0300

Gnomad4 FIN exome AF: 0.000599

Gnomad4 NFE exome AF: 0.00840

Gnomad4 OTH exome AF: 0.0182

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

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0177

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0321

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00891

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0157 Hom.: 118

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -

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
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	4.6
Dann	Benign	0.39
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
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
Polyphen		0.0	.;B;.;B
Vest4		0.057, 0.097
MPC		0.35
ClinPred		0.0028	T
GERP RS		-1.1
Varity_R		0.043
gMVP		0.47

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: rs35507522; hg19: chr11-120973430;