rs876658014

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005422.4(TECTA):c.2537G>A(p.Gly846Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.72

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TECTA	NM_005422.4 linkuse as main transcript	c.2537G>A	p.Gly846Glu	missense_variant	10/24	ENST00000392793.6
TBCEL-TECTA	NM_001378761.1 linkuse as main transcript	c.3494G>A	p.Gly1165Glu	missense_variant	16/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TECTA	ENST00000392793.6 linkuse as main transcript	c.2537G>A	p.Gly846Glu	missense_variant	10/24	5	NM_005422.4	P4
TECTA	ENST00000264037.2 linkuse as main transcript	c.2537G>A	p.Gly846Glu	missense_variant	9/23	1		P4
TECTA	ENST00000642222.1 linkuse as main transcript	c.2537G>A	p.Gly846Glu	missense_variant	10/24			A1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 18, 2017

The p.Gly846Glu variant in TECTA has been previously reported 1 individual with hearing loss and segregated in 2 affected family members. This variant has also been identified in 1/15012 European chromosomes by the Genome Aggregation Databa se (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analyses do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Gly846Glu variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.22

T;.;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.7

L;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

N;.;N

REVEL

Benign

0.23

Sift

Benign

0.35

T;.;T

Sift4G

Benign

0.14

T;.;T

Polyphen

0.88

P;.;P

Vest4

0.66

MutPred

0.66

Loss of catalytic residue at C849 (P = 0.1738);Loss of catalytic residue at C849 (P = 0.1738);Loss of catalytic residue at C849 (P = 0.1738);

MVP

0.84

MPC

0.63

ClinPred

0.72

GERP RS

4.6

Varity_R

0.23

gMVP

0.93

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

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