rs41258944

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.9562G>A(p.Val3188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,612,640 control chromosomes in the GnomAD database, including 3,258 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 0.068 ( 416 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2842 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0390

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=0.0017081797).

BP6

Variant 6-32049465-C-T is Benign according to our data. Variant chr6-32049465-C-T is described in ClinVar as Benign. ClinVar VariationId is 261178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.9562G>A	p.Val3188Ile	missense_variant	Exon 28 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.10303G>A	p.Val3435Ile	missense_variant	Exon 29 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.9556G>A	p.Val3186Ile	missense_variant	Exon 28 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.9562G>A	p.Val3188Ile	missense_variant	Exon 28 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.10303G>A	p.Val3435Ile	missense_variant	Exon 29 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.9562G>A	p.Val3188Ile	missense_variant	Exon 28 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0676

AC:

10283

AN:

152098

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.0362

Gnomad ASJ

AF:

0.0692

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.0605

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0598

Gnomad OTH

AF:

0.0636

GnomAD2 exomes

AF:

0.0484

AC:

11881

AN:

245582

AF XY:

0.0496

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0290

Gnomad ASJ exome

AF:

0.0720

Gnomad EAS exome

AF:

0.00290

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.0539

Gnomad OTH exome

AF:

0.0479

GnomAD4 exome

AF:

0.0585

AC:

85459

AN:

1460424

Hom.:

2842

Cov.:

AF XY:

0.0578

AC XY:

42006

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.117

AC:

3925

AN:

33446

American (AMR)

AF:

0.0317

AC:

1416

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0739

AC:

1931

AN:

26136

East Asian (EAS)

AF:

0.00224

AC:

AN:

39700

South Asian (SAS)

AF:

0.0548

AC:

4722

AN:

86222

European-Finnish (FIN)

AF:

0.0211

AC:

1117

AN:

52958

Middle Eastern (MID)

AF:

0.0499

AC:

255

AN:

5110

European-Non Finnish (NFE)

AF:

0.0613

AC:

68181

AN:

1111846

Other (OTH)

AF:

0.0634

AC:

3823

AN:

60282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

6513

13026

19540

26053

32566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2644

5288

7932

10576

13220

<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:

0.0676

AC:

10291

AN:

152216

Hom.:

416

Cov.:

AF XY:

0.0644

AC XY:

4790

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.111

AC:

4610

AN:

41516

American (AMR)

AF:

0.0362

AC:

553

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0692

AC:

240

AN:

3470

East Asian (EAS)

AF:

0.00888

AC:

AN:

5180

South Asian (SAS)

AF:

0.0599

AC:

289

AN:

4826

European-Finnish (FIN)

AF:

0.0188

AC:

199

AN:

10610

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0598

AC:

4064

AN:

68002

Other (OTH)

AF:

0.0630

AC:

133

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

482

964

1447

1929

2411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0652

Hom.:

151

Bravo

AF:

0.0714

TwinsUK

AF:

0.0601

AC:

223

ALSPAC

AF:

0.0586

AC:

226

ESP6500AA

AF:

0.113

AC:

283

ESP6500EA

AF:

0.0622

AC:

313

ExAC

AF:

0.0494

AC:

5915

EpiCase

AF:

0.0623

EpiControl

AF:

0.0580

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

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 11, 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

0.084

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.35

.;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-0.84

PhyloP100

0.039

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.62

.;.;N;.

REVEL

Benign

0.14

Sift

Benign

0.22

.;.;T;.

Sift4G

Benign

0.21

.;.;T;T

Vest4

0.076

ClinPred

0.0063

GERP RS

3.5

Varity_R

0.028

Mutation Taster

=98/2

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