NM_005422.4:c.6062G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_005422.4(TECTA):c.6062G>A(p.Arg2021His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.56

Variant links:

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]

TECTA links:

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]

TBCEL-TECTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a disulfide_bond (size 55) in uniprot entity TECTA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005422.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 11-121187894-G-A is Pathogenic according to our data. Variant chr11-121187894-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-121187894-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TECTA	NM_005422.4 link	c.6062G>A	p.Arg2021His	missense_variant	Exon 21 of 24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 link	c.7004G>A	p.Arg2335His	missense_variant	Exon 27 of 30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TECTA	ENST00000392793.6 link	c.6062G>A	p.Arg2021His	missense_variant	Exon 21 of 24	5	NM_005422.4	ENSP00000376543.1		O75443

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251478

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000454

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Jun 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TECTA function (PMID: 22718023). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TECTA protein function. ClinVar contains an entry for this variant (Variation ID: 7021). This missense change has been observed in individual(s) with autosomal dominant nonsyndromic deafness and/or clinical features of TECTA-related conditions (PMID: 12162770; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121909062, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2021 of the TECTA protein (p.Arg2021His). -

Feb 02, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss

Pathogenic:1

Oct 16, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg2021His variant in TECTA has been reported in 4 individuals with hearing loss and segregated with disease in 4 affected family members across two families (Iwasaki 2002 PMID: 12162770, Lin 2021 PMID: 34325055, Invitae pers. comm., LMM unpublished data). It was reported to have occurred de novo in one of the affected individuals (Invitae pers. comm.). The variant was absent from large population studies. It has been reported in ClinVar (Variation ID 7021). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts localization of the protein (Moteki 2012 PMID: 22718023); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic hearing loss. ACMG/AMP Criteria applied: PS4, PM6_Supporting, PM2_Supporting, PP1_Moderate, PP3, PS3_Supporting. -

Autosomal dominant nonsyndromic hearing loss 12

Pathogenic:1

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.2

M;.;M

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.3

N;.;N

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

D;.;D

Sift4G

Uncertain

0.0030

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.96

MutPred

0.92

Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);

MVP

0.94

MPC

1.2

ClinPred

0.99

GERP RS

5.7

Varity_R

0.45

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over