6-32058330-C-T

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.7553G>A(p.Gly2518Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,611,184 control chromosomes in the GnomAD database, including 409,280 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. G2518G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.69 ( 36743 hom., cov: 31)

Exomes 𝑓: 0.71 ( 372537 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.350

Publications

45 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=9.462437E-7).

BP6

Variant 6-32058330-C-T is Benign according to our data. Variant chr6-32058330-C-T is described in ClinVar as Benign. ClinVar VariationId is 261162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.7553G>A	p.Gly2518Glu	missense_variant	Exon 22 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.8294G>A	p.Gly2765Glu	missense_variant	Exon 23 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.7553G>A	p.Gly2518Glu	missense_variant	Exon 22 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TNXB	ENST00000644971.2 link	c.7553G>A	p.Gly2518Glu	missense_variant	Exon 22 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1 link	c.8294G>A	p.Gly2765Glu	missense_variant	Exon 23 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7 link	c.7553G>A	p.Gly2518Glu	missense_variant	Exon 22 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes

AF:

0.692

AC:

104635

AN:

151308

Hom.:

36712

Cov.:

show subpopulations

Gnomad AFR

AF:

0.635

Gnomad AMI

AF:

0.737

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.852

Gnomad EAS

AF:

0.634

Gnomad SAS

AF:

0.748

Gnomad FIN

AF:

0.651

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.707

Gnomad OTH

AF:

0.722

GnomAD2 exomes

AF:

0.720

AC:

173470

AN:

240990

AF XY:

0.724

show subpopulations

Gnomad AFR exome

AF:

0.639

Gnomad AMR exome

AF:

0.783

Gnomad ASJ exome

AF:

0.848

Gnomad EAS exome

AF:

0.617

Gnomad FIN exome

AF:

0.651

Gnomad NFE exome

AF:

0.711

Gnomad OTH exome

AF:

0.724

GnomAD4 exome

AF:

0.713

AC:

1040295

AN:

1459760

Hom.:

372537

Cov.:

AF XY:

0.716

AC XY:

519633

AN XY:

726150

show subpopulations

African (AFR)

AF:

0.647

AC:

21615

AN:

33410

American (AMR)

AF:

0.783

AC:

34953

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.845

AC:

22063

AN:

26124

East Asian (EAS)

AF:

0.655

AC:

25994

AN:

39690

South Asian (SAS)

AF:

0.775

AC:

66874

AN:

86244

European-Finnish (FIN)

AF:

0.648

AC:

33653

AN:

51958

Middle Eastern (MID)

AF:

0.772

AC:

4447

AN:

5764

European-Non Finnish (NFE)

AF:

0.709

AC:

787688

AN:

1111586

Other (OTH)

AF:

0.713

AC:

43008

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

17460

34919

52379

69838

87298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19810

39620

59430

79240

99050

<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:

0.692

AC:

104717

AN:

151424

Hom.:

36743

Cov.:

AF XY:

0.691

AC XY:

51152

AN XY:

74010

show subpopulations

African (AFR)

AF:

0.635

AC:

25977

AN:

40892

American (AMR)

AF:

0.761

AC:

11627

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.852

AC:

2958

AN:

3470

East Asian (EAS)

AF:

0.635

AC:

3275

AN:

5156

South Asian (SAS)

AF:

0.746

AC:

3589

AN:

4812

European-Finnish (FIN)

AF:

0.651

AC:

6871

AN:

10562

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.707

AC:

48012

AN:

67952

Other (OTH)

AF:

0.719

AC:

1509

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1570

3141

4711

6282

7852

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

820

1640

2460

3280

4100

<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:

0.708

Hom.:

19963

Bravo

AF:

0.699

TwinsUK

AF:

0.714

AC:

2647

ALSPAC

AF:

0.710

AC:

2736

ESP6500AA

AF:

0.652

AC:

1507

ESP6500EA

AF:

0.701

AC:

3513

ExAC

AF:

0.714

AC:

83884

Asia WGS

AF:

0.693

AC:

2414

AN:

3478

EpiCase

AF:

0.730

EpiControl

AF:

0.732

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vesicoureteral reflux 8

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 04, 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

0.047

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.077

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.022

T;.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00094

LIST_S2

Benign

0.034

.;T;T;T

MetaRNN

Benign

9.5e-7

T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

-0.35

PrimateAI

Benign

0.33

PROVEAN

Benign

2.3

.;.;N;.

REVEL

Benign

0.024

Sift

Benign

1.0

.;.;T;.

Sift4G

Benign

1.0

.;.;T;T

Vest4

0.025

ClinPred

0.0011

GERP RS

3.3

Varity_R

0.025

Mutation Taster

=99/1

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