rs200821009

Positions:

chr11-121137446-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_005422.4(TECTA):c.2967C>A(p.His989Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,978 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.0640

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:):

TBCEL-TECTA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.072065145).

BP6

Variant 11-121137446-C-A is Benign according to our data. Variant chr11-121137446-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505413.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000986 (15/152092) while in subpopulation EAS AF= 0.00295 (15/5084). AF 95% confidence interval is 0.00182. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4 linkuse as main transcript	c.2967C>A	p.His989Gln	missense_variant	11/24	ENST00000392793.6	NP_005413.2
TBCEL-TECTA	NM_001378761.1 linkuse as main transcript	c.3924C>A	p.His1308Gln	missense_variant	17/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TECTA	ENST00000392793.6 linkuse as main transcript	c.2967C>A	p.His989Gln	missense_variant	11/24	5	NM_005422.4	ENSP00000376543	P4
TECTA	ENST00000264037.2 linkuse as main transcript	c.2967C>A	p.His989Gln	missense_variant	10/23	1		ENSP00000264037	P4
TECTA	ENST00000642222.1 linkuse as main transcript	c.2967C>A	p.His989Gln	missense_variant	11/24			ENSP00000493855	A1
TECTA	ENST00000645008.1 linkuse as main transcript	c.276C>A	p.His92Gln	missense_variant	2/15			ENSP00000496274

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00294

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251114

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00207

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00169

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00295

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000652

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2024	Identified in patients with sensorineural hearing loss in published literature, however, the hearing loss may have been due to a variant in a different gene in all cases (PMID: 24655070, 33924653); 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: 24655070, 33924653, 21520338, 31554319, 9590290) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 06, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.His989Gln var iant in TECTA has been reported in 1 Japanese family with hearing loss; however, the hearing loss was likely due to a variant in a different gene (Ishikawa 2014 ). This variant has been identified in 0.2% of East Asian chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200821 009). Computational prediction tools and conservation analysis suggest that the p.His989Gln variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, while the clinical signific ance of the p.His989Gln variant is uncertain, these data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.75

D;.;D

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.79

.;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Benign

1.8

L;.;L

MutationTaster

Benign

0.69

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.7

D;.;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

1.0

D;.;D

Vest4

0.81

MutPred

0.41

Gain of disorder (P = 0.0973);Gain of disorder (P = 0.0973);Gain of disorder (P = 0.0973);

MVP

0.72

MPC

1.1

ClinPred

0.43

GERP RS

-3.3

Varity_R

0.91

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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