6-32096321-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.1532G>A(p.Arg511His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,548,246 control chromosomes in the GnomAD database, including 13,959 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 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. R511R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 2281 hom., cov: 34)

Exomes 𝑓: 0.11 ( 11678 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.146

Publications

18 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=0.0062685013).

BP6

Variant 6-32096321-C-T is Benign according to our data. Variant chr6-32096321-C-T is described in ClinVar as Benign. ClinVar VariationId is 261125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.1532G>A	p.Arg511His	missense_variant	Exon 3 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.1532G>A	p.Arg511His	missense_variant	Exon 3 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.1532G>A	p.Arg511His	missense_variant	Exon 3 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.1532G>A	p.Arg511His	missense_variant	Exon 3 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes

AF:

0.150

AC:

22858

AN:

152132

Hom.:

2268

Cov.:

show subpopulations

Gnomad AFR

AF:

0.258

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.289

Gnomad FIN

AF:

0.0623

Gnomad MID

AF:

0.247

Gnomad NFE

AF:

0.0945

Gnomad OTH

AF:

0.187

GnomAD2 exomes

AF:

0.147

AC:

21664

AN:

146980

AF XY:

0.161

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.0701

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.140

GnomAD4 exome

AF:

0.109

AC:

152312

AN:

1395996

Hom.:

11678

Cov.:

AF XY:

0.116

AC XY:

80076

AN XY:

689910

show subpopulations

African (AFR)

AF:

0.266

AC:

8477

AN:

31866

American (AMR)

AF:

0.106

AC:

3894

AN:

36610

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

2701

AN:

25288

East Asian (EAS)

AF:

0.108

AC:

3888

AN:

36166

South Asian (SAS)

AF:

0.330

AC:

26379

AN:

79956

European-Finnish (FIN)

AF:

0.0697

AC:

2641

AN:

37912

Middle Eastern (MID)

AF:

0.256

AC:

1459

AN:

5696

European-Non Finnish (NFE)

AF:

0.0883

AC:

95708

AN:

1084208

Other (OTH)

AF:

0.123

AC:

7165

AN:

58294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

10316

20632

30949

41265

51581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3672

7344

11016

14688

18360

<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:

0.150

AC:

22895

AN:

152250

Hom.:

2281

Cov.:

AF XY:

0.153

AC XY:

11409

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.259

AC:

10763

AN:

41538

American (AMR)

AF:

0.148

AC:

2265

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

371

AN:

3472

East Asian (EAS)

AF:

0.105

AC:

546

AN:

5180

South Asian (SAS)

AF:

0.289

AC:

1395

AN:

4826

European-Finnish (FIN)

AF:

0.0623

AC:

662

AN:

10618

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0945

AC:

6424

AN:

68004

Other (OTH)

AF:

0.184

AC:

388

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1010

2020

3031

4041

5051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.109

Hom.:

2539

Bravo

AF:

0.157

TwinsUK

AF:

0.0852

AC:

316

ALSPAC

AF:

0.0947

AC:

365

ESP6500AA

AF:

0.229

AC:

940

ESP6500EA

AF:

0.0855

AC:

694

ExAC

AF:

0.107

AC:

11845

Asia WGS

AF:

0.244

AC:

851

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

0.095

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;T;.;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.032

LIST_S2

Uncertain

0.90

.;D;D;D;D

MetaRNN

Benign

0.0063

T;T;T;T;T

MetaSVM

Benign

-0.98

PhyloP100

0.15

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.8

.;.;D;.;D

REVEL

Benign

0.054

Sift

Benign

0.032

.;.;D;.;D

Sift4G

Uncertain

0.0030

.;.;D;D;D

Vest4

0.099, 0.17

ClinPred

0.027

GERP RS

2.3

Varity_R

0.17

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