11-121125600-C-T

Position:

chr11-121125600-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005422.4(TECTA):c.1502C>T(p.Ser501Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000856 in 1,613,846 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00088 ( 2 hom. )

Consequence

TECTA
NM_005422.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.90

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043305725).

BP6

Variant 11-121125600-C-T is Benign according to our data. Variant chr11-121125600-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178535.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TECTA	NM_005422.4 linkuse as main transcript	c.1502C>T	p.Ser501Phe	missense_variant	8/24	ENST00000392793.6	NP_005413.2	O75443
TBCEL-TECTA	NM_001378761.1 linkuse as main transcript	c.2459C>T	p.Ser820Phe	missense_variant	14/30		NP_001365690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TECTA	ENST00000392793.6 linkuse as main transcript	c.1502C>T	p.Ser501Phe	missense_variant	8/24	5	NM_005422.4	ENSP00000376543.1	O75443
TECTA	ENST00000264037.2 linkuse as main transcript	c.1502C>T	p.Ser501Phe	missense_variant	7/23	1		ENSP00000264037.2	O75443
TECTA	ENST00000642222.1 linkuse as main transcript	c.1502C>T	p.Ser501Phe	missense_variant	8/24			ENSP00000493855.1	A0A2R8YDL0

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000490

AC:

123

AN:

251108

Hom.:

AF XY:

0.000516

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000898

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000883

AC:

1291

AN:

1461492

Hom.:

Cov.:

AF XY:

0.000854

AC XY:

621

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000563

Gnomad4 NFE exome

AF:

0.00111

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000597

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000527

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2024	Identified as a single heterozygous variant in a patient with non-syndromic hearing loss in published literature; reported as a likely benign variant (PMID: 27068579); 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: 21520338, 9590290, 31554319, 34515852, 27068579) -

Autosomal recessive nonsyndromic hearing loss 21

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 26, 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. -

Autosomal dominant nonsyndromic hearing loss 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 06, 2018

The p.Ser501Phe variant in TECTA is classified as likely benign because it has n ot been reported in the literature, but has been identified in 0.26% (7/2670) of Bulgarian chromosomes and 0.09% (116/128954) of all European chromosomes by gno mAD (http://gnomad.broadinstitute.org). Furthermore, computational prediction to ols and conservation analysis suggest that this variant may not impact the prote in. ACMG/AMP Criteria applied: BS1_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;.;D

Eigen

Benign

0.041

Eigen_PC

Benign

0.084

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

N;.;N

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

D;.;D

REVEL

Benign

0.11

Sift

Uncertain

0.023

D;.;D

Sift4G

Uncertain

0.027

D;.;D

Polyphen

0.43

B;.;B

Vest4

0.43

MVP

0.69

MPC

0.40

ClinPred

0.050

GERP RS

5.0

Varity_R

0.25

gMVP

0.81

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