6-32079167-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365276.2(TNXB):c.4241G>A(p.Arg1414Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,816 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1414W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.033 ( 157 hom., cov: 32)

Exomes 𝑓: 0.020 ( 503 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.27

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome due to tenascin-X deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
familial vesicoureteral reflux
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
vesicoureteral reflux 8
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TNXB links:

ENSG00000294466 (HGNC:):

ENSG00000294466 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019538403).

BP6

Variant 6-32079167-C-T is Benign according to our data. Variant chr6-32079167-C-T is described in ClinVar as Benign. ClinVar VariationId is 261138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.4241G>A	p.Arg1414Gln	missense_variant	Exon 11 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.4982G>A	p.Arg1661Gln	missense_variant	Exon 12 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.4241G>A	p.Arg1414Gln	missense_variant	Exon 11 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.4241G>A	p.Arg1414Gln	missense_variant	Exon 11 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0335

AC:

5092

AN:

152196

Hom.:

158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0667

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0351

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.0614

Gnomad SAS

AF:

0.0408

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0431

GnomAD2 exomes

AF:

0.0272

AC:

6735

AN:

247422

AF XY:

0.0276

show subpopulations

Gnomad AFR exome

AF:

0.0673

Gnomad AMR exome

AF:

0.0260

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.0777

Gnomad FIN exome

AF:

0.00311

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0197

AC:

28781

AN:

1461502

Hom.:

503

Cov.:

AF XY:

0.0202

AC XY:

14722

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.0664

AC:

2223

AN:

33476

American (AMR)

AF:

0.0270

AC:

1208

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26134

East Asian (EAS)

AF:

0.0332

AC:

1317

AN:

39700

South Asian (SAS)

AF:

0.0436

AC:

3763

AN:

86254

European-Finnish (FIN)

AF:

0.00379

AC:

202

AN:

53360

Middle Eastern (MID)

AF:

0.0284

AC:

160

AN:

5632

European-Non Finnish (NFE)

AF:

0.0164

AC:

18283

AN:

1111866

Other (OTH)

AF:

0.0217

AC:

1307

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1802

3605

5407

7210

9012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0335

AC:

5099

AN:

152314

Hom.:

157

Cov.:

AF XY:

0.0328

AC XY:

2444

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0666

AC:

2766

AN:

41558

American (AMR)

AF:

0.0350

AC:

536

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.0617

AC:

320

AN:

5184

South Asian (SAS)

AF:

0.0412

AC:

199

AN:

4830

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0163

AC:

1108

AN:

68020

Other (OTH)

AF:

0.0426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

246

492

737

983

1229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0203

Hom.:

Bravo

AF:

0.0369

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.0626

AC:

161

ESP6500EA

AF:

0.0186

AC:

ExAC

AF:

0.0278

AC:

3356

Asia WGS

AF:

0.0390

AC:

134

AN:

3478

EpiCase

AF:

0.0188

EpiControl

AF:

0.0214

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Jul 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 18, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

0.056

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.67

CADD

Benign

9.9

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.022

T;.;T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.37

.;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-0.97

PhyloP100

1.3

PrimateAI

Benign

0.32

PROVEAN

Benign

1.7

.;.;N;.

REVEL

Benign

0.15

Sift

Benign

1.0

.;.;T;.

Sift4G

Benign

1.0

.;.;T;T

Vest4

0.021

ClinPred

0.0013

GERP RS

4.3

Varity_R

0.030

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over