6-32053637-C-T

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.8542G>A(p.Gly2848Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,382 control chromosomes in the GnomAD database, including 962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2848G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 142 hom., cov: 31)

Exomes 𝑓: 0.023 ( 820 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.52

Publications

15 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=0.0023582876).

BP6

Variant 6-32053637-C-T is Benign according to our data. Variant chr6-32053637-C-T is described in ClinVar as Benign. ClinVar VariationId is 261169.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 = 0.0243 (3699/152204) while in subpopulation NFE AF = 0.0246 (1675/67996). AF 95% confidence interval is 0.0237. There are 142 homozygotes in GnomAd4. There are 2145 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 142 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.8542G>A	p.Gly2848Arg	missense_variant	Exon 25 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.9283G>A	p.Gly3095Arg	missense_variant	Exon 26 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.8536G>A	p.Gly2846Arg	missense_variant	Exon 25 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TNXB	ENST00000644971.2 link	c.8542G>A	p.Gly2848Arg	missense_variant	Exon 25 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1 link	c.9283G>A	p.Gly3095Arg	missense_variant	Exon 26 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7 link	c.8542G>A	p.Gly2848Arg	missense_variant	Exon 25 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3698

AN:

152086

Hom.:

142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.00863

GnomAD2 exomes

AF:

0.0246

AC:

6047

AN:

245848

AF XY:

0.0240

show subpopulations

Gnomad AFR exome

AF:

0.00403

Gnomad AMR exome

AF:

0.00519

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.135

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0203

GnomAD4 exome

AF:

0.0229

AC:

33428

AN:

1461178

Hom.:

820

Cov.:

AF XY:

0.0223

AC XY:

16194

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

33470

American (AMR)

AF:

0.00546

AC:

244

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26134

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.00632

AC:

545

AN:

86256

European-Finnish (FIN)

AF:

0.129

AC:

6862

AN:

53000

Middle Eastern (MID)

AF:

0.00454

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.0222

AC:

24665

AN:

1111822

Other (OTH)

AF:

0.0160

AC:

965

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

2274

4548

6823

9097

11371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.0243

AC:

3699

AN:

152204

Hom.:

142

Cov.:

AF XY:

0.0288

AC XY:

2145

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41542

American (AMR)

AF:

0.0100

AC:

153

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.00892

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.147

AC:

1556

AN:

10586

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0246

AC:

1675

AN:

67996

Other (OTH)

AF:

0.00854

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

179

359

538

718

897

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0126

Hom.:

Bravo

AF:

0.0127

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00762

AC:

ESP6500EA

AF:

0.0242

AC:

125

ExAC

AF:

0.0233

AC:

2808

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0181

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 17, 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 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 24, 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

0.18

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

.;.;.;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.87

.;D;T;D

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-0.82

PhyloP100

3.5

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.6

.;.;D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

.;.;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D

Vest4

0.19

ClinPred

0.033

GERP RS

4.4

Varity_R

0.34

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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