6-32042349-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001365276.2(TNXB):c.12224G>A(p.Arg4075His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4075L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0068 ( 1 hom., cov: 19)

Exomes 𝑓: 0.045 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.08

Publications

15 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005153835).

BP6

Variant 6-32042349-C-T is Benign according to our data. Variant chr6-32042349-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190375.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.12224G>A	p.Arg4075His	missense_variant	Exon 41 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.12965G>A	p.Arg4322His	missense_variant	Exon 42 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.12218G>A	p.Arg4073His	missense_variant	Exon 41 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681
TNXB	NM_032470.4 link	c.1511G>A	p.Arg504His	missense_variant	Exon 10 of 13		NP_115859.2	P22105-2Q6IPK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.12224G>A	p.Arg4075His	missense_variant	Exon 41 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00683

AC:

848

AN:

124242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00120

Gnomad AMR

AF:

0.00474

Gnomad ASJ

AF:

0.00129

Gnomad EAS

AF:

0.00705

Gnomad SAS

AF:

0.0136

Gnomad FIN

AF:

0.00403

Gnomad MID

AF:

0.0149

Gnomad NFE

AF:

0.00387

Gnomad OTH

AF:

0.00646

GnomAD2 exomes

AF:

0.0317

AC:

6690

AN:

210924

AF XY:

0.0355

show subpopulations

Gnomad AFR exome

AF:

0.0688

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0445

AC:

55050

AN:

1236720

Hom.:

Cov.:

AF XY:

0.0430

AC XY:

26655

AN XY:

619428

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.111

AC:

2701

AN:

24320

American (AMR)

AF:

0.0179

AC:

699

AN:

39016

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

491

AN:

22816

East Asian (EAS)

AF:

0.0194

AC:

669

AN:

34510

South Asian (SAS)

AF:

0.0609

AC:

4535

AN:

74514

European-Finnish (FIN)

AF:

0.00695

AC:

348

AN:

50078

Middle Eastern (MID)

AF:

0.0210

AC:

107

AN:

5092

European-Non Finnish (NFE)

AF:

0.0463

AC:

43303

AN:

935224

Other (OTH)

AF:

0.0430

AC:

2197

AN:

51150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.289

Heterozygous variant carriers

4604

9209

13813

18418

23022

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

2290

4580

6870

9160

11450

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00684

AC:

850

AN:

124342

Hom.:

Cov.:

AF XY:

0.00681

AC XY:

413

AN XY:

60682

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0150

AC:

421

AN:

28094

American (AMR)

AF:

0.00474

AC:

AN:

12882

Ashkenazi Jewish (ASJ)

AF:

0.00129

AC:

AN:

3090

East Asian (EAS)

AF:

0.00730

AC:

AN:

4384

South Asian (SAS)

AF:

0.0130

AC:

AN:

3538

European-Finnish (FIN)

AF:

0.00403

AC:

AN:

9670

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

254

European-Non Finnish (NFE)

AF:

0.00387

AC:

232

AN:

59874

Other (OTH)

AF:

0.00637

AC:

AN:

1726

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

108

217

325

434

542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0163

Hom.:

ExAC

AF:

0.0869

AC:

10532

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency

Uncertain:1Benign:1

Jan 01, 2015

Pediatric Services, National Institutes of Health, Clinical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Mar 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

May 21, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;.;.;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

.;T;T;D;D

MetaRNN

Benign

0.0052

T;T;T;T;T

MetaSVM

Pathogenic

0.89

PhyloP100

3.1

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.4

.;.;D;D;.

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D;D

Vest4

0.21, 0.72

MPC

3.4

ClinPred

0.072

GERP RS

4.8

Varity_R

0.67

gMVP

0.92

Mutation Taster

=92/8

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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