rs142486386

chr11-121137576-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005422.4(TECTA):c.3097C>T(p.Arg1033Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,930 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1033Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:6
• Conservation: PhyloP100: 1.51

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=0.015393078).
• BP6: Variant 11-121137576-C-T is Benign according to our data. Variant chr11-121137576-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178538.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0014 (213/152038) while in subpopulation AMR AF= 0.00419 (64/15278). AF 95% confidence interval is 0.00337. There are 2 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4	c.3097C>T	p.Arg1033Trp	missense_variant	11/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1	c.4054C>T	p.Arg1352Trp	missense_variant	17/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TECTA	ENST00000392793.6	c.3097C>T	p.Arg1033Trp	missense_variant	11/24	5	NM_005422.4	P4
TECTA	ENST00000264037.2	c.3097C>T	p.Arg1033Trp	missense_variant	10/23	1		P4
TECTA	ENST00000642222.1	c.3097C>T	p.Arg1033Trp	missense_variant	11/24			A1
TECTA	ENST00000645008.1	c.406C>T	p.Arg136Trp	missense_variant	2/15

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 212 AN: 151920 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000974

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251328 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135826

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000200 AC: 293 AN: 1461892 Hom.: 1 Cov.: 32 AF XY: 0.000176 AC XY: 128 AN XY: 727248

Gnomad4 AFR exome AF: 0.00349

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000881

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152038 Hom.: 2 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 74324

Gnomad4 AFR AF: 0.00323

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000976

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000283 Hom.: 0

Bravo AF: 0.00188

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2021	Identified in a patient with hearing loss who was also heterozygous for the Q234R variant (Sloan-Heggen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26969326) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2017	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 22, 2017	p.Arg1033Trp in exon 10 of TECTA: This variant is not expected to have clinical significance because it has been identified in 0.3% (81/24020) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs142486386). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2021	Variant summary: TECTA c.3097C>T (p.Arg1033Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282672 control chromosomes, predominantly at a frequency of 0.0035 within the African or African-American subpopulation in the gnomAD database. This frequency is equal to the estimated maximal expected allele frequency of a pathogenic variant in TECTA causing Deafness, Autosomal Recessive 21 (0.0035 vs 0.0035), suggesting this may be a benign polymorphism. c.3097C>T has been reported in the literature in one individual affected with hearing loss (Sloan-Heggen_2016). The report does not provide unequivocal conclusions about association of the variant with Deafness, Autosomal Recessive 21. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=4), including one expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2018	The p.Arg1033Trp variant (rs142486386) has been reported in the medical literature in a single individual with a suspected diagnosis of non-syndromic hearing loss; however, inheritance and specific clinical information were not reported for this individual (Sloan-Heggen 2016). The p.Arg1033Trp variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.34% in the African population (identified in 81 out of 24,020 chromosomes), and is listed in the ClinVar database (Variant ID: 178538). The arginine at codon 1033 is highly conserved considering 11 species up to Tetraodon (Alamut software v2.10.0), and computational analyses suggest that this variant does affect the structure/function of the TECTA protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). While the p.Arg1033Trp variant appears to be an ethnic specific polymorphism in the African population, the available evidence is insufficient to classify this variant with certainty. -

Nonsyndromic genetic hearing loss Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Apr 29, 2019

The filtering allele frequency (the lower threshold of the 95% CI of 88/24956) of the p.Arg1033Trp variant in the TECTA gene is 0.29% for African chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The p.Arg1033Trp variant has been identified in one hearing loss patient who carries a second TECTA variant, p.Gln234Arg, that has previously been classified as likely benign by the HL VCEP (PMID 26969326, SCV000840522.3). The variant has also been observed by Partners LMM in one homozygous patient, two heterozygous patients, and two compound heterozygous patients who also carry one or two pathogenic or VUS favor-pathogenic variants. These cases are inconclusive (SCV000204966.4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1. -

TECTA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;.;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.2	M;.;M
MutationTaster	Benign	0.84	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;.;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.027	D;.;D
Sift4G	Pathogenic	0.0010	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.85
MVP		0.92
MPC		1.0
ClinPred		0.037	T
GERP RS		4.3
Varity_R		0.29
gMVP		0.72

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: rs142486386; hg19: chr11-121008285; COSMIC: COSV50692425; COSMIC: COSV50692425;