rs118086587

Positions:

chr6-32096384-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365276.2(TNXB):c.1469G>A(p.Arg490Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,560,144 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 21 hom., cov: 34)

Exomes 𝑓: 0.0046 ( 127 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.285

Variant links:

Genes affected

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003249526).

BP6

Variant 6-32096384-C-T is Benign according to our data. Variant chr6-32096384-C-T is described in ClinVar as [Benign]. Clinvar id is 261124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32096384-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00575 (845/146998) while in subpopulation AMR AF= 0.0323 (478/14800). AF 95% confidence interval is 0.0299. There are 21 homozygotes in gnomad4. There are 483 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.1469G>A	p.Arg490Gln	missense_variant	3/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.1469G>A	p.Arg490Gln	missense_variant	3/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.1469G>A	p.Arg490Gln	missense_variant	3/44		NM_001365276.2	ENSP00000496448		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00571

AC:

839

AN:

146858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0319

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0219

Gnomad SAS

AF:

0.000433

Gnomad FIN

AF:

0.00699

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00401

GnomAD3 exomes

AF:

0.0115

AC:

2003

AN:

174274

Hom.:

AF XY:

0.00871

AC XY:

843

AN XY:

96810

show subpopulations

Gnomad AFR exome

AF:

0.000542

Gnomad AMR exome

AF:

0.0529

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0172

Gnomad SAS exome

AF:

0.000401

Gnomad FIN exome

AF:

0.00783

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.00564

GnomAD4 exome

AF:

0.00459

AC:

6493

AN:

1413146

Hom.:

127

Cov.:

AF XY:

0.00423

AC XY:

2965

AN XY:

700216

show subpopulations

Gnomad4 AFR exome

AF:

0.000493

Gnomad4 AMR exome

AF:

0.0452

Gnomad4 ASJ exome

AF:

0.0000788

Gnomad4 EAS exome

AF:

0.0425

Gnomad4 SAS exome

AF:

0.000344

Gnomad4 FIN exome

AF:

0.00689

Gnomad4 NFE exome

AF:

0.00242

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.00575

AC:

845

AN:

146998

Hom.:

Cov.:

AF XY:

0.00672

AC XY:

483

AN XY:

71882

show subpopulations

Gnomad4 AFR

AF:

0.000351

Gnomad4 AMR

AF:

0.0323

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0219

Gnomad4 SAS

AF:

0.000434

Gnomad4 FIN

AF:

0.00699

Gnomad4 NFE

AF:

0.00254

Gnomad4 OTH

AF:

0.00395

Alfa

AF:

0.00274

Hom.:

Bravo

AF:

0.00686

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.00636

AC:

742

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 22, 2022

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 07, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

T;.;T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.069

LIST_S2

Uncertain

0.88

.;D;D;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.8

.;.;N;.;N

REVEL

Benign

0.091

Sift

Benign

0.30

.;.;T;.;T

Sift4G

Uncertain

0.034

.;.;D;T;T

Vest4

0.26, 0.14

ClinPred

0.022

GERP RS

2.3

Varity_R

0.082

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