rs17207895

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365276.2(TNXB):c.9050A>G(p.Lys3017Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,740 control chromosomes in the GnomAD database, including 751 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 93 hom., cov: 32)

Exomes 𝑓: 0.020 ( 658 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.71

Publications

7 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=0.0028343797).

BP6

Variant 6-32052735-T-C is Benign according to our data. Variant chr6-32052735-T-C is described in ClinVar as Benign. ClinVar VariationId is 261173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0198 (3011/152226) while in subpopulation NFE AF = 0.0239 (1626/68008). AF 95% confidence interval is 0.0229. There are 93 homozygotes in GnomAd4. There are 1466 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 93 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.9050A>G	p.Lys3017Arg	missense_variant	Exon 26 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.9791A>G	p.Lys3264Arg	missense_variant	Exon 27 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.9044A>G	p.Lys3015Arg	missense_variant	Exon 26 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.9050A>G	p.Lys3017Arg	missense_variant	Exon 26 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.9791A>G	p.Lys3264Arg	missense_variant	Exon 27 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.9050A>G	p.Lys3017Arg	missense_variant	Exon 26 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0198

AC:

3012

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0204

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0239

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0239

AC:

5899

AN:

246360

AF XY:

0.0243

show subpopulations

Gnomad AFR exome

AF:

0.00163

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.163

Gnomad EAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.0207

Gnomad NFE exome

AF:

0.0269

Gnomad OTH exome

AF:

0.0308

GnomAD4 exome

AF:

0.0200

AC:

29197

AN:

1461514

Hom.:

658

Cov.:

AF XY:

0.0205

AC XY:

14886

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00284

AC:

AN:

33480

American (AMR)

AF:

0.0145

AC:

650

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

3988

AN:

26136

East Asian (EAS)

AF:

0.00103

AC:

AN:

39700

South Asian (SAS)

AF:

0.00435

AC:

375

AN:

86254

European-Finnish (FIN)

AF:

0.0210

AC:

1115

AN:

53220

Middle Eastern (MID)

AF:

0.0218

AC:

126

AN:

5768

European-Non Finnish (NFE)

AF:

0.0192

AC:

21314

AN:

1111860

Other (OTH)

AF:

0.0247

AC:

1493

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1733

3466

5198

6931

8664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.0198

AC:

3011

AN:

152226

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

1466

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41538

American (AMR)

AF:

0.0204

AC:

312

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

608

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5160

South Asian (SAS)

AF:

0.00415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0221

AC:

235

AN:

10620

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0239

AC:

1626

AN:

68008

Other (OTH)

AF:

0.0241

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

155

310

464

619

774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00657

Hom.:

Bravo

AF:

0.0193

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00453

AC:

ESP6500EA

AF:

0.0239

AC:

123

ExAC

AF:

0.0224

AC:

2709

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0345

EpiControl

AF:

0.0357

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Ehlers-Danlos syndrome

Benign:1

Apr 01, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 21, 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

0.099

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

.;.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.71

.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.7

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

.;.;N;.

REVEL

Benign

0.14

Sift

Benign

0.26

.;.;T;.

Sift4G

Benign

0.19

.;.;T;T

Vest4

0.13

ClinPred

0.018

GERP RS

3.2

Varity_R

0.085

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