rs113926083

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_001365276.2(TNXB):c.10893G>A(p.Lys3631Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 148,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 0 hom., cov: 25)

Exomes 𝑓: 0.068 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.747

Publications

4 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 6-32045040-C-T is Benign according to our data. Variant chr6-32045040-C-T is described in ClinVar as Benign. ClinVar VariationId is 261099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.747 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.10893G>A	p.Lys3631Lys	synonymous_variant	Exon 32 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.11634G>A	p.Lys3878Lys	synonymous_variant	Exon 33 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.10887G>A	p.Lys3629Lys	synonymous_variant	Exon 32 of 44		NP_061978.6
TNXB	NM_032470.4 link	c.180G>A	p.Lys60Lys	synonymous_variant	Exon 1 of 13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.10893G>A	p.Lys3631Lys	synonymous_variant	Exon 32 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes

AF:

0.0493

AC:

7308

AN:

148344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.103

Gnomad AMR

AF:

0.0442

Gnomad ASJ

AF:

0.121

Gnomad EAS

AF:

0.00468

Gnomad SAS

AF:

0.0227

Gnomad FIN

AF:

0.0336

Gnomad MID

AF:

0.0946

Gnomad NFE

AF:

0.0763

Gnomad OTH

AF:

0.0517

GnomAD2 exomes

AF:

0.0526

AC:

12016

AN:

228440

AF XY:

0.0539

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0316

Gnomad ASJ exome

AF:

0.124

Gnomad EAS exome

AF:

0.00660

Gnomad FIN exome

AF:

0.0369

Gnomad NFE exome

AF:

0.0770

Gnomad OTH exome

AF:

0.0650

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0683

AC:

95093

AN:

1391566

Hom.:

Cov.:

AF XY:

0.0681

AC XY:

47162

AN XY:

693038

show subpopulations

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

African (AFR)

AF:

0.0104

AC:

346

AN:

33174

American (AMR)

AF:

0.0334

AC:

1449

AN:

43404

Ashkenazi Jewish (ASJ)

AF:

0.126

AC:

3095

AN:

24500

East Asian (EAS)

AF:

0.00997

AC:

372

AN:

37320

South Asian (SAS)

AF:

0.0263

AC:

2214

AN:

84132

European-Finnish (FIN)

AF:

0.0388

AC:

1977

AN:

50996

Middle Eastern (MID)

AF:

0.0890

AC:

485

AN:

5450

European-Non Finnish (NFE)

AF:

0.0770

AC:

81213

AN:

1054722

Other (OTH)

AF:

0.0681

AC:

3942

AN:

57868

⚠️ 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: 0.287

Heterozygous variant carriers

8189

16378

24567

32756

40945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2912

5824

8736

11648

14560

<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:

0.0492

AC:

7307

AN:

148460

Hom.:

Cov.:

AF XY:

0.0470

AC XY:

3412

AN XY:

72642

show subpopulations

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

African (AFR)

AF:

0.0133

AC:

548

AN:

41268

American (AMR)

AF:

0.0442

AC:

656

AN:

14854

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

393

AN:

3236

East Asian (EAS)

AF:

0.00469

AC:

AN:

5112

South Asian (SAS)

AF:

0.0231

AC:

110

AN:

4752

European-Finnish (FIN)

AF:

0.0336

AC:

349

AN:

10384

Middle Eastern (MID)

AF:

0.0912

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0763

AC:

5008

AN:

65664

Other (OTH)

AF:

0.0511

AC:

105

AN:

2054

⚠️ 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: 0.307

Heterozygous variant carriers

474

947

1421

1894

2368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

168

252

336

420

<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:

0.0830

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

6.4

(source)

DANN

Benign

0.87

PhyloP100

-0.75

Mutation Taster

=97/3

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

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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