NM_001365276.2:c.6379G>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.6379G>A(p.Val2127Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,126 control chromosomes in the GnomAD database, including 15,033 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2127G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.15 ( 2194 hom., cov: 32)

Exomes 𝑓: 0.11 ( 12839 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.28

Publications

12 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=0.0061406195).

BP6

Variant 6-32067826-C-T is Benign according to our data. Variant chr6-32067826-C-T is described in ClinVar as Benign. ClinVar VariationId is 261147.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	UniProt
TNXB	NM_001365276.2 link	c.6379G>A	p.Val2127Met	missense_variant	Exon 18 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.7120G>A	p.Val2374Met	missense_variant	Exon 19 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.6379G>A	p.Val2127Met	missense_variant	Exon 18 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.6379G>A	p.Val2127Met	missense_variant	Exon 18 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.7120G>A	p.Val2374Met	missense_variant	Exon 19 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.6379G>A	p.Val2127Met	missense_variant	Exon 18 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.149

AC:

22573

AN:

152004

Hom.:

2183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.249

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.147

Gnomad ASJ

AF:

0.110

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.0625

Gnomad MID

AF:

0.248

Gnomad NFE

AF:

0.0960

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.139

AC:

34607

AN:

248520

AF XY:

0.151

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.0963

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.0659

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.111

AC:

162430

AN:

1461004

Hom.:

12839

Cov.:

AF XY:

0.119

AC XY:

86359

AN XY:

726804

show subpopulations

African (AFR)

AF:

0.257

AC:

8608

AN:

33470

American (AMR)

AF:

0.103

AC:

4599

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

2849

AN:

26134

East Asian (EAS)

AF:

0.109

AC:

4340

AN:

39700

South Asian (SAS)

AF:

0.343

AC:

29568

AN:

86234

European-Finnish (FIN)

AF:

0.0686

AC:

3656

AN:

53332

Middle Eastern (MID)

AF:

0.254

AC:

1328

AN:

5234

European-Non Finnish (NFE)

AF:

0.0899

AC:

99979

AN:

1111858

Other (OTH)

AF:

0.124

AC:

7503

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

11231

22461

33692

44922

56153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3792

7584

11376

15168

18960

<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:

0.149

AC:

22607

AN:

152122

Hom.:

2194

Cov.:

AF XY:

0.152

AC XY:

11290

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.249

AC:

10344

AN:

41474

American (AMR)

AF:

0.147

AC:

2245

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.110

AC:

383

AN:

3468

East Asian (EAS)

AF:

0.106

AC:

548

AN:

5160

South Asian (SAS)

AF:

0.296

AC:

1429

AN:

4824

European-Finnish (FIN)

AF:

0.0625

AC:

663

AN:

10600

Middle Eastern (MID)

AF:

0.226

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0960

AC:

6531

AN:

68000

Other (OTH)

AF:

0.181

AC:

383

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

934

1868

2801

3735

4669

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:

0.114

Hom.:

395

Bravo

AF:

0.155

ESP6500AA

AF:

0.240

AC:

904

ESP6500EA

AF:

0.0939

AC:

767

ExAC

AF:

0.147

AC:

17726

Asia WGS

AF:

0.247

AC:

859

AN:

3478

EpiCase

AF:

0.103

EpiControl

AF:

0.104

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

0.30

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.64

.;T;T

MetaRNN

Benign

0.0061

T;T;T

MetaSVM

Benign

-0.90

PhyloP100

-1.3

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

.;.;N

REVEL

Benign

0.19

Sift

Benign

0.042

.;.;D

Sift4G

Uncertain

0.0020

.;.;D

Vest4

0.12

ClinPred

0.054

GERP RS

-0.99

Varity_R

0.051

Mutation Taster

=100/0

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