NM_001365276.2:c.5713G>A

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.5713G>A(p.Glu1905Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,612,862 control chromosomes in the GnomAD database, including 658 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E1905E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 170 hom., cov: 32)

Exomes 𝑓: 0.021 ( 488 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0580

Publications

13 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=0.0020450354).

BP6

Variant 6-32069011-C-T is Benign according to our data. Variant chr6-32069011-C-T is described in ClinVar as Benign. ClinVar VariationId is 261143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.5713G>A	p.Glu1905Lys	missense_variant	Exon 16 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.6454G>A	p.Glu2152Lys	missense_variant	Exon 17 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.5713G>A	p.Glu1905Lys	missense_variant	Exon 16 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.5713G>A	p.Glu1905Lys	missense_variant	Exon 16 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.6454G>A	p.Glu2152Lys	missense_variant	Exon 17 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.5713G>A	p.Glu1905Lys	missense_variant	Exon 16 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0377

AC:

5737

AN:

152178

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0792

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0489

GnomAD2 exomes

AF:

0.0211

AC:

5148

AN:

244330

AF XY:

0.0198

show subpopulations

Gnomad AFR exome

AF:

0.0800

Gnomad AMR exome

AF:

0.0299

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00112

Gnomad FIN exome

AF:

0.00246

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0317

GnomAD4 exome

AF:

0.0207

AC:

30184

AN:

1460566

Hom.:

488

Cov.:

AF XY:

0.0199

AC XY:

14490

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.0871

AC:

2916

AN:

33478

American (AMR)

AF:

0.0330

AC:

1477

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0283

AC:

740

AN:

26136

East Asian (EAS)

AF:

0.000806

AC:

AN:

39700

South Asian (SAS)

AF:

0.00876

AC:

756

AN:

86258

European-Finnish (FIN)

AF:

0.00319

AC:

167

AN:

52282

Middle Eastern (MID)

AF:

0.0323

AC:

186

AN:

5766

European-Non Finnish (NFE)

AF:

0.0203

AC:

22590

AN:

1111862

Other (OTH)

AF:

0.0219

AC:

1320

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1799

3599

5398

7198

8997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.0377

AC:

5735

AN:

152296

Hom.:

170

Cov.:

AF XY:

0.0364

AC XY:

2711

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0790

AC:

3282

AN:

41554

American (AMR)

AF:

0.0490

AC:

750

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3472

East Asian (EAS)

AF:

0.00290

AC:

AN:

5180

South Asian (SAS)

AF:

0.00663

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0207

AC:

1410

AN:

68022

Other (OTH)

AF:

0.0479

AC:

101

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

273

547

820

1094

1367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0244

Hom.:

220

Bravo

AF:

0.0436

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.0659

AC:

178

ESP6500EA

AF:

0.0220

AC:

114

ExAC

AF:

0.0212

AC:

2495

Asia WGS

AF:

0.00722

AC:

AN:

3478

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

Jun 02, 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 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 21, 2019

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

0.091

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.76

.;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.98

PhyloP100

0.058

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

.;.;N

REVEL

Benign

0.12

Sift

Benign

0.17

.;.;T

Sift4G

Uncertain

0.015

.;.;D

Vest4

0.16

ClinPred

0.065

GERP RS

-1.9

Varity_R

0.26

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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