rs377156351

Positions:

• chr11-121158168-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005422.4(TECTA):​c.4633G>A​(p.Val1545Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,613,898 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 3.26

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]

TECTA (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15999064).
• BP6: Variant 11-121158168-G-A is Benign according to our data. Variant chr11-121158168-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45333.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr11-121158168-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.4633G>A	p.Val1545Ile	missense_variant	14/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.5590G>A	p.Val1864Ile	missense_variant	20/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.4633G>A	p.Val1545Ile	missense_variant	14/24	5	NM_005422.4	ENSP00000376543.1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000310 AC: 78 AN: 251346 Hom.: 0 AF XY: 0.000383 AC XY: 52 AN XY: 135872

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000295 AC: 431 AN: 1461748 Hom.: 1 Cov.: 32 AF XY: 0.000333 AC XY: 242 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000466 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31554319, 9590290, 21520338) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TECTA: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 05, 2013

Variant classified as Uncertain Significance - Favor Benign. The 4633G>A Val1545 Ile variant in TECTA has not been previously identified by our laboratory but ha s been seen in 0.02% (2/8598) of European American chromosomes by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT ) do not provide strong support for or against an impact to the protein, though one mammal, Pika, carries the same variant in its normal sequence, suggesting a less likely impact to protein function. It should be noted that both recessive a nd dominant mutations have been described for TECTA, with recessive variants pri marily loss of function and dominant typically missense variants. Although the c linical significance of this variant is unknown, we would lean towards a more li kely benign role given the lack of amino acid conservation across all mammals. -

Autosomal dominant nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 25, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L;.;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.71	N;.;N
REVEL	Benign	0.18
Sift	Benign	0.082	T;.;T
Sift4G	Uncertain	0.019	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.25
MVP		0.68
MPC		0.74
ClinPred		0.26	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.26

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: rs377156351; hg19: chr11-121028877; COSMIC: COSV50698136;