6-32095904-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.1949G>A(p.Arg650His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,612,498 control chromosomes in the GnomAD database, including 3,433 homozygotes. In-silico tool predicts 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. R650G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.080 ( 675 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2758 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.57

Publications

10 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:

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=0.0016717613).

BP6

Variant 6-32095904-C-T is Benign according to our data. Variant chr6-32095904-C-T is described in ClinVar as [Benign]. Clinvar id is 261127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.1949G>A	p.Arg650His	missense_variant	Exon 3 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.1949G>A	p.Arg650His	missense_variant	Exon 3 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.1949G>A	p.Arg650His	missense_variant	Exon 3 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.1949G>A	p.Arg650His	missense_variant	Exon 3 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0800

AC:

12179

AN:

152150

Hom.:

676

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0966

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.0404

Gnomad SAS

AF:

0.0824

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0467

Gnomad OTH

AF:

0.109

GnomAD2 exomes

AF:

0.0607

AC:

14485

AN:

238816

AF XY:

0.0615

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.0602

Gnomad ASJ exome

AF:

0.0775

Gnomad EAS exome

AF:

0.0459

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.0486

Gnomad OTH exome

AF:

0.0722

GnomAD4 exome

AF:

0.0518

AC:

75700

AN:

1460230

Hom.:

2758

Cov.:

AF XY:

0.0530

AC XY:

38468

AN XY:

726366

show subpopulations

African (AFR)

AF:

0.162

AC:

5406

AN:

33454

American (AMR)

AF:

0.0658

AC:

2933

AN:

44558

Ashkenazi Jewish (ASJ)

AF:

0.0800

AC:

2084

AN:

26050

East Asian (EAS)

AF:

0.0274

AC:

1086

AN:

39668

South Asian (SAS)

AF:

0.0966

AC:

8320

AN:

86144

European-Finnish (FIN)

AF:

0.0124

AC:

656

AN:

52838

Middle Eastern (MID)

AF:

0.175

AC:

1007

AN:

5764

European-Non Finnish (NFE)

AF:

0.0454

AC:

50473

AN:

1111452

Other (OTH)

AF:

0.0619

AC:

3735

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

5670

11340

17010

22680

28350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1996

3992

5988

7984

9980

<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:

0.0800

AC:

12178

AN:

152268

Hom.:

675

Cov.:

AF XY:

0.0796

AC XY:

5928

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.150

AC:

6244

AN:

41544

American (AMR)

AF:

0.0965

AC:

1477

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3470

East Asian (EAS)

AF:

0.0405

AC:

210

AN:

5182

South Asian (SAS)

AF:

0.0827

AC:

399

AN:

4824

European-Finnish (FIN)

AF:

0.0109

AC:

116

AN:

10628

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0467

AC:

3173

AN:

68000

Other (OTH)

AF:

0.107

AC:

225

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

564

1127

1691

2254

2818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<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:

0.0546

Hom.:

795

Bravo

AF:

0.0897

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.132

AC:

553

ESP6500EA

AF:

0.0481

AC:

405

ExAC

AF:

0.0627

AC:

7575

Asia WGS

AF:

0.0770

AC:

270

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

not provided

Benign:1

Sep 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 14, 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

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;T;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.84

.;T;T;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

1.6

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.1

.;.;D;.;D

REVEL

Benign

0.11

Sift

Benign

0.055

.;.;T;.;D

Sift4G

Uncertain

0.0030

.;.;D;D;D

Vest4

0.25, 0.23

ClinPred

0.022

GERP RS

4.3

Varity_R

0.29

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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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