6-32061406-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.7483G>A(p.Gly2495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 1,612,046 control chromosomes in the GnomAD database, including 14,412 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1844 hom., cov: 32)

Exomes 𝑓: 0.11 ( 12568 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.02

Publications

41 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=0.006383598).

BP6

Variant 6-32061406-C-T is Benign according to our data. Variant chr6-32061406-C-T is described in ClinVar as Benign. ClinVar VariationId is 261161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.7483G>A	p.Gly2495Ser	missense_variant	Exon 21 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.8224G>A	p.Gly2742Ser	missense_variant	Exon 22 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.7483G>A	p.Gly2495Ser	missense_variant	Exon 21 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TNXB	ENST00000644971.2 link	c.7483G>A	p.Gly2495Ser	missense_variant	Exon 21 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1 link	c.8224G>A	p.Gly2742Ser	missense_variant	Exon 22 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7 link	c.7483G>A	p.Gly2495Ser	missense_variant	Exon 21 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20203

AN:

151562

Hom.:

1839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.201

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.136

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.296

Gnomad FIN

AF:

0.0623

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.0949

Gnomad OTH

AF:

0.168

GnomAD2 exomes

AF:

0.135

AC:

33104

AN:

245182

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.0884

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.0658

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.109

AC:

159380

AN:

1460366

Hom.:

12568

Cov.:

AF XY:

0.117

AC XY:

84958

AN XY:

726370

show subpopulations

African (AFR)

AF:

0.211

AC:

7061

AN:

33388

American (AMR)

AF:

0.0949

AC:

4238

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

2845

AN:

26090

East Asian (EAS)

AF:

0.109

AC:

4339

AN:

39676

South Asian (SAS)

AF:

0.342

AC:

29499

AN:

86226

European-Finnish (FIN)

AF:

0.0682

AC:

3615

AN:

53014

Middle Eastern (MID)

AF:

0.264

AC:

1523

AN:

5764

European-Non Finnish (NFE)

AF:

0.0891

AC:

99022

AN:

1111212

Other (OTH)

AF:

0.120

AC:

7238

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

8388

16777

25165

33554

41942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3738

7476

11214

14952

18690

<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:

0.133

AC:

20227

AN:

151680

Hom.:

1844

Cov.:

AF XY:

0.137

AC XY:

10158

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.202

AC:

8280

AN:

41056

American (AMR)

AF:

0.135

AC:

2067

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

383

AN:

3466

East Asian (EAS)

AF:

0.104

AC:

535

AN:

5166

South Asian (SAS)

AF:

0.295

AC:

1418

AN:

4802

European-Finnish (FIN)

AF:

0.0623

AC:

662

AN:

10622

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0949

AC:

6450

AN:

67980

Other (OTH)

AF:

0.166

AC:

349

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

833

1666

2500

3333

4166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.112

Hom.:

3411

Bravo

AF:

0.138

TwinsUK

AF:

0.0836

AC:

310

ALSPAC

AF:

0.0947

AC:

365

ESP6500AA

AF:

0.171

AC:

479

ESP6500EA

AF:

0.0869

AC:

452

ExAC

AF:

0.141

AC:

17066

Asia WGS

AF:

0.241

AC:

840

AN:

3476

EpiCase

AF:

0.102

EpiControl

AF:

0.102

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Ehlers-Danlos syndrome

Benign:1

Jul 14, 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

This variant is associated with the following publications: (PMID: 16574953)

Cardiovascular phenotype

Benign:1

Dec 31, 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

0.19

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.071

T;.;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.0

.;T;T;T

MetaRNN

Benign

0.0064

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

2.0

PrimateAI

Benign

0.42

PROVEAN

Benign

0.0

.;.;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;T;.

Sift4G

Pathogenic

0.0

.;.;D;D

Vest4

0.0

ClinPred

0.071

GERP RS

4.4

Varity_R

0.097

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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