9-115041016-C-T

Position:

chr9-115041016-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The ENST00000350763.9(TNC):c.5317G>A(p.Val1773Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

TNC
ENST00000350763.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.807

Variant links:

Genes affected

TNC (HGNC:5318): (tenascin C) This gene encodes an extracellular matrix protein with a spatially and temporally restricted tissue distribution. This protein is homohexameric with disulfide-linked subunits, and contains multiple EGF-like and fibronectin type-III domains. It is implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity, and neuronal regeneration. [provided by RefSeq, Jul 2011]

TNC links:

DELEC1 (HGNC:23658): (deleted in esophageal cancer 1) The function of this gene is not known. This gene is located in a region commonly deleted in esophageal squamous cell carcinomas. Gene expression is reduced or absent in these carcinomas and thus this is a candidate tumor suppressor gene for esophageal squamous cell carcinomas. [provided by RefSeq, Jul 2008]

DELEC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 9-115041016-C-T is Pathogenic according to our data. Variant chr9-115041016-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97008.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr9-115041016-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.04226744). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNC	NM_002160.4 linkuse as main transcript	c.5317G>A	p.Val1773Met	missense_variant	19/28	ENST00000350763.9	NP_002151.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNC	ENST00000350763.9 linkuse as main transcript	c.5317G>A	p.Val1773Met	missense_variant	19/28	1	NM_002160.4	ENSP00000265131	P1	P24821-1
DELEC1	ENST00000649121.1 linkuse as main transcript	n.79-43239C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

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:

0.0000441

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251398

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000752

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:

0.0000967

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000256

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000835

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 56

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Jun 10, 2024	Pathogenic by Deafness Variation Datatbase based on PMID: 23936043 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 30, 2013	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T;.;T;.;.

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.85

T;D;T;D;D;.

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.042

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

.;N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.097

.;T;T;T;D;D

Sift4G

Uncertain

0.048

D;D;D;T;T;D

Polyphen

0.13, 0.78

.;B;.;P;.;.

Vest4

0.15

MVP

0.52

MPC

0.18

ClinPred

0.018

GERP RS

1.1

Varity_R

0.10

gMVP

0.61

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