NM_001365276.2:c.607G>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.607G>A(p.Val203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,608,376 control chromosomes in the GnomAD database, including 2,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 593 hom., cov: 33)

Exomes 𝑓: 0.047 ( 2320 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00700

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=0.005492538).

BP6

Variant 6-32097246-C-T is Benign according to our data. Variant chr6-32097246-C-T is described in ClinVar as Benign. ClinVar VariationId is 261145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.607G>A	p.Val203Met	missense_variant	Exon 3 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.607G>A	p.Val203Met	missense_variant	Exon 3 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.607G>A	p.Val203Met	missense_variant	Exon 3 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.607G>A	p.Val203Met	missense_variant	Exon 3 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0744

AC:

11323

AN:

152178

Hom.:

594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0919

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.0235

Gnomad SAS

AF:

0.0715

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0439

Gnomad OTH

AF:

0.102

GnomAD2 exomes

AF:

0.0536

AC:

12753

AN:

238026

AF XY:

0.0542

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.0552

Gnomad ASJ exome

AF:

0.0769

Gnomad EAS exome

AF:

0.0185

Gnomad FIN exome

AF:

0.00974

Gnomad NFE exome

AF:

0.0448

Gnomad OTH exome

AF:

0.0672

GnomAD4 exome

AF:

0.0473

AC:

68831

AN:

1456080

Hom.:

2320

Cov.:

AF XY:

0.0482

AC XY:

34916

AN XY:

723850

show subpopulations

African (AFR)

AF:

0.152

AC:

5059

AN:

33376

American (AMR)

AF:

0.0602

AC:

2619

AN:

43540

Ashkenazi Jewish (ASJ)

AF:

0.0792

AC:

2055

AN:

25954

East Asian (EAS)

AF:

0.0125

AC:

495

AN:

39488

South Asian (SAS)

AF:

0.0845

AC:

7207

AN:

85312

European-Finnish (FIN)

AF:

0.0113

AC:

599

AN:

52980

Middle Eastern (MID)

AF:

0.167

AC:

964

AN:

5756

European-Non Finnish (NFE)

AF:

0.0418

AC:

46399

AN:

1109486

Other (OTH)

AF:

0.0571

AC:

3434

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

4974

9948

14921

19895

24869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1818

3636

5454

7272

9090

<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:

0.0743

AC:

11319

AN:

152296

Hom.:

593

Cov.:

AF XY:

0.0737

AC XY:

5490

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.140

AC:

5817

AN:

41554

American (AMR)

AF:

0.0918

AC:

1405

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0818

AC:

284

AN:

3472

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5190

South Asian (SAS)

AF:

0.0717

AC:

346

AN:

4824

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10616

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0439

AC:

2983

AN:

68018

Other (OTH)

AF:

0.100

AC:

212

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

525

1049

1574

2098

2623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0544

Hom.:

261

Bravo

AF:

0.0833

TwinsUK

AF:

0.0383

AC:

142

ALSPAC

AF:

0.0459

AC:

177

ESP6500AA

AF:

0.122

AC:

529

ESP6500EA

AF:

0.0456

AC:

387

ExAC

AF:

0.0545

AC:

6604

Asia WGS

AF:

0.0590

AC:

209

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

Jan 14, 2019

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

0.20

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;.;T;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.97

.;D;D;D;D

MetaRNN

Benign

0.0055

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.0070

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.9

.;.;N;.;N

REVEL

Benign

0.17

Sift

Benign

0.10

.;.;T;.;D

Sift4G

Uncertain

0.0030

.;.;D;D;D

Vest4

0.12, 0.34

ClinPred

0.012

GERP RS

4.2

Varity_R

0.064

Mutation Taster

=94/6

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