rs138768918

Positions:

• chr11-121145754-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005422.4(TECTA):​c.3743C>T​(p.Pro1248Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,614,170 control chromosomes in the GnomAD database, including 1 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 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: TECTA NM_005422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: 2.30

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14338759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4	c.3743C>T	p.Pro1248Leu	missense_variant	12/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1	c.4700C>T	p.Pro1567Leu	missense_variant	18/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6	c.3743C>T	p.Pro1248Leu	missense_variant	12/24	5	NM_005422.4	ENSP00000376543.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251492 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135920

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000483

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1461894 Hom.: 1 Cov.: 31 AF XY: 0.000320 AC XY: 233 AN XY: 727248

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000375

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74468

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TECTA: PM2:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27368438, 24586623, 25262649, 27068579, 30245029, 31554319, 9590290, 21520338, 34008892) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Autosomal recessive nonsyndromic hearing loss 21 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM2, PP2, PP3, PP4, PP5 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in 1 proband with HL, at most 1 segregation. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Supporting, PM2_Supporting -

TECTA-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 2024

The TECTA c.3743C>T variant is predicted to result in the amino acid substitution p.Pro1248Leu. This variant has been reported in individuals with non-syndromic autosomal dominant hearing loss (Table 1, Hildebrand et al. 2011. PubMed ID: 21520338; Shearer et al. 2014. PubMed ID: 25262649; Table S1, Sommen et al. 2016. PubMed ID: 27068579; Table 1, Marinakis et al. 2021. PubMed ID: 34008892). In ClinVar, this variant has conflicting interpretations ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/403527; Table S3, Azaiez et al. 2018. PubMed ID: 30245029). It has also been interpreted as benign based on population frequency in another variant interpretation study (Table S4, Shearer et al. 2014. PubMed ID: 25262649). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 0.08% of alleles in Ashkenazi Jewish descendants, including 1 homozygote and a total of 518 alleles globally. This population data is not consistent with this variant being a primary cause of autosomal dominant disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant nonsyndromic hearing loss 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.1	D;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.020	D;.;D
Sift4G	Benign	0.093	T;.;T
Polyphen		0.17	B;.;B
Vest4		0.30
MVP		0.75
MPC		0.43
ClinPred		0.61	D
GERP RS		5.8
Varity_R		0.36
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: rs138768918; hg19: chr11-121016463;