rs1150752

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.904A>G(p.Thr302Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,611,064 control chromosomes in the GnomAD database, including 9,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 457 hom., cov: 33)

Exomes 𝑓: 0.10 ( 9420 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.174

Publications

52 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=0.0038123429).

BP6

Variant 6-32096949-T-C is Benign according to our data. Variant chr6-32096949-T-C is described in ClinVar as Benign. ClinVar VariationId is 261174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.904A>G	p.Thr302Ala	missense_variant	Exon 3 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.904A>G	p.Thr302Ala	missense_variant	Exon 3 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.904A>G	p.Thr302Ala	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.904A>G	p.Thr302Ala	missense_variant	Exon 3 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0624

AC:

9413

AN:

150772

Hom.:

457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0710

Gnomad AMR

AF:

0.0292

Gnomad ASJ

AF:

0.0388

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0806

Gnomad MID

AF:

0.0195

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.0470

GnomAD2 exomes

AF:

0.0589

AC:

14500

AN:

246382

AF XY:

0.0579

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.0215

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.0000559

Gnomad FIN exome

AF:

0.0779

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0600

GnomAD4 exome

AF:

0.101

AC:

147319

AN:

1460176

Hom.:

9420

Cov.:

AF XY:

0.0975

AC XY:

70835

AN XY:

726260

show subpopulations

African (AFR)

AF:

0.0140

AC:

466

AN:

33402

American (AMR)

AF:

0.0221

AC:

986

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.0400

AC:

1043

AN:

26070

East Asian (EAS)

AF:

0.000101

AC:

AN:

39668

South Asian (SAS)

AF:

0.000209

AC:

AN:

86006

European-Finnish (FIN)

AF:

0.0808

AC:

4304

AN:

53276

Middle Eastern (MID)

AF:

0.00555

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.122

AC:

135253

AN:

1111138

Other (OTH)

AF:

0.0864

AC:

5213

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

9471

18942

28414

37885

47356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4908

9816

14724

19632

24540

<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:

0.0624

AC:

9410

AN:

150888

Hom.:

457

Cov.:

AF XY:

0.0579

AC XY:

4273

AN XY:

73744

show subpopulations

African (AFR)

AF:

0.0155

AC:

635

AN:

40938

American (AMR)

AF:

0.0291

AC:

442

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.0388

AC:

134

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4764

European-Finnish (FIN)

AF:

0.0806

AC:

842

AN:

10442

Middle Eastern (MID)

AF:

0.0208

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.106

AC:

7189

AN:

67704

Other (OTH)

AF:

0.0466

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

447

895

1342

1790

2237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<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:

0.0779

Hom.:

819

Bravo

AF:

0.0567

TwinsUK

AF:

0.129

AC:

480

ALSPAC

AF:

0.129

AC:

497

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.106

AC:

900

ExAC

AF:

0.0589

AC:

7141

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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

Dec 24, 2018

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

0.075

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.4

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.071

T;.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.22

.;T;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.17

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.6

.;.;N;.;D

REVEL

Benign

0.037

Sift

Benign

0.067

.;.;T;.;T

Sift4G

Benign

0.094

.;.;T;T;T

Vest4

0.040, 0.082

ClinPred

0.0062

GERP RS

-2.2

Varity_R

0.086

Mutation Taster

=99/1

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