NM_001365276.2:c.517G>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.517G>A(p.Ala173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,613,458 control chromosomes in the GnomAD database, including 1,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 62 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1300 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.08

Publications

6 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=0.0015425086).

BP6

Variant 6-32097336-C-T is Benign according to our data. Variant chr6-32097336-C-T is described in ClinVar as Benign. ClinVar VariationId is 261140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNXB	NM_001365276.2	MANE Select	c.517G>A	p.Ala173Thr	missense	Exon 3 of 44	NP_001352205.1
TNXB	NM_001428335.1		c.517G>A	p.Ala173Thr	missense	Exon 3 of 45	NP_001415264.1
TNXB	NM_019105.8		c.517G>A	p.Ala173Thr	missense	Exon 3 of 44	NP_061978.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNXB	ENST00000644971.2	MANE Select	c.517G>A	p.Ala173Thr	missense	Exon 3 of 44	ENSP00000496448.1
TNXB	ENST00000479795.1	TSL:1	c.517G>A	p.Ala173Thr	missense	Exon 3 of 5	ENSP00000418248.1
TNXB	ENST00000486148.1	TSL:1	n.912G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3024

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00975

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.0550

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0347

AC:

8613

AN:

247940

AF XY:

0.0398

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.00728

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.0526

Gnomad FIN exome

AF:

0.0205

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0259

AC:

37797

AN:

1461162

Hom.:

1300

Cov.:

AF XY:

0.0289

AC XY:

21019

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00935

AC:

313

AN:

33478

American (AMR)

AF:

0.00734

AC:

328

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

385

AN:

26132

East Asian (EAS)

AF:

0.0746

AC:

2962

AN:

39700

South Asian (SAS)

AF:

0.127

AC:

10960

AN:

86246

European-Finnish (FIN)

AF:

0.0209

AC:

1105

AN:

52912

Middle Eastern (MID)

AF:

0.0168

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0180

AC:

19982

AN:

1111842

Other (OTH)

AF:

0.0276

AC:

1665

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

2493

4986

7480

9973

12466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

834

1668

2502

3336

4170

<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:

0.0198

AC:

3023

AN:

152296

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1662

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0106

AC:

440

AN:

41562

American (AMR)

AF:

0.00974

AC:

149

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3468

East Asian (EAS)

AF:

0.0550

AC:

285

AN:

5184

South Asian (SAS)

AF:

0.114

AC:

549

AN:

4828

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10618

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0194

AC:

1317

AN:

68014

Other (OTH)

AF:

0.0151

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

155

310

464

619

774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0196

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.0119

AC:

ESP6500EA

AF:

0.0171

AC:

144

ExAC

AF:

0.0364

AC:

4403

Asia WGS

AF:

0.136

AC:

470

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0189

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.51

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.030

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

PhyloP100

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.68

REVEL

Benign

0.14

Sift

Benign

0.79

Sift4G

Benign

0.76

Vest4

0.021

ClinPred

0.0026

GERP RS

-8.8

Varity_R

0.029

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over