rs204885

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_001365276.2(TNXB):c.7168+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0364 in 1,609,336 control chromosomes in the GnomAD database, including 1,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 189 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1150 hom. )

Consequence

TNXB
NM_001365276.2 splice_region, intron

Scores

Splicing: ADA: 0.9956

Clinical Significance

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

Conservation

PhyloP100: 4.37

Publications

6 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
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 -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 6-32062152-C-T is Benign according to our data. Variant chr6-32062152-C-T is described in ClinVar as Benign. ClinVar VariationId is 261154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNXB	NM_001365276.2	MANE Select	c.7168+5G>A	splice_region intron	N/A	NP_001352205.1	P22105-3
TNXB	NM_001428335.1		c.7909+5G>A	splice_region intron	N/A	NP_001415264.1	A0A3B3ISX9
TNXB	NM_019105.8		c.7168+5G>A	splice_region intron	N/A	NP_061978.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNXB	ENST00000644971.2	MANE Select	c.7168+5G>A	splice_region intron	N/A	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1		c.7909+5G>A	splice_region intron	N/A	ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7	TSL:5	c.7168+5G>A	splice_region intron	N/A	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0432

AC:

6579

AN:

152232

Hom.:

190

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0806

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0480

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00263

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0337

Gnomad OTH

AF:

0.0454

GnomAD2 exomes

AF:

0.0251

AC:

6118

AN:

243866

AF XY:

0.0233

show subpopulations

Gnomad AFR exome

AF:

0.0808

Gnomad AMR exome

AF:

0.0337

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00369

Gnomad NFE exome

AF:

0.0308

Gnomad OTH exome

AF:

0.0333

GnomAD4 exome

AF:

0.0357

AC:

52050

AN:

1456986

Hom.:

1150

Cov.:

AF XY:

0.0338

AC XY:

24476

AN XY:

724008

show subpopulations

African (AFR)

AF:

0.0794

AC:

2652

AN:

33396

American (AMR)

AF:

0.0356

AC:

1585

AN:

44546

Ashkenazi Jewish (ASJ)

AF:

0.0142

AC:

371

AN:

26040

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39600

South Asian (SAS)

AF:

0.000291

AC:

AN:

86008

European-Finnish (FIN)

AF:

0.00429

AC:

225

AN:

52456

Middle Eastern (MID)

AF:

0.00765

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0407

AC:

45108

AN:

1108974

Other (OTH)

AF:

0.0338

AC:

2038

AN:

60214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2733

5467

8200

10934

13667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1830

3660

5490

7320

9150

<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:

0.0432

AC:

6585

AN:

152350

Hom.:

189

Cov.:

AF XY:

0.0408

AC XY:

3042

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0805

AC:

3346

AN:

41572

American (AMR)

AF:

0.0480

AC:

734

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00263

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0337

AC:

2295

AN:

68038

Other (OTH)

AF:

0.0449

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

316

631

947

1262

1578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0358

Hom.:

Bravo

AF:

0.0497

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0335

EpiControl

AF:

0.0332

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

4.4

PromoterAI

-0.23

Neutral

(source)

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over