rs1135809

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001428335.1(TNXB):c.12662A>C(p.Asn4221Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 32 hom., cov: 0)

Exomes 𝑓: 0.40 ( 26836 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001428335.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.346

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=8.867399E-6).

BP6

Variant 6-32042955-T-G is Benign according to our data. Variant chr6-32042955-T-G is described in ClinVar as Benign. ClinVar VariationId is 261117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001428335.1. 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.11921A>C	p.Asn3974Thr	missense	Exon 38 of 44	NP_001352205.1
TNXB	NM_001428335.1		c.12662A>C	p.Asn4221Thr	missense	Exon 39 of 45	NP_001415264.1
TNXB	NM_019105.8		c.11915A>C	p.Asn3972Thr	missense	Exon 38 of 44	NP_061978.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNXB	ENST00000644971.2	MANE Select	c.11921A>C	p.Asn3974Thr	missense	Exon 38 of 44	ENSP00000496448.1
TNXB	ENST00000451343.4	TSL:1	c.1208A>C	p.Asn403Thr	missense	Exon 7 of 13	ENSP00000407685.1
TNXB	ENST00000490077.5	TSL:1	n.1748A>C		non_coding_transcript_exon	Exon 8 of 14

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

282

AN:

1832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0866

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.217

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.0965

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.250

Gnomad MID

AF:

0.0500

Gnomad NFE

AF:

0.192

Gnomad OTH

AF:

0.132

GnomAD2 exomes

AF:

0.398

AC:

21125

AN:

53052

AF XY:

0.395

show subpopulations

Gnomad AFR exome

AF:

0.252

Gnomad AMR exome

AF:

0.522

Gnomad ASJ exome

AF:

0.652

Gnomad EAS exome

AF:

0.241

Gnomad FIN exome

AF:

0.351

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.421

GnomAD4 exome

AF:

0.399

AC:

126635

AN:

317224

Hom.:

26836

Cov.:

AF XY:

0.398

AC XY:

66392

AN XY:

166918

show subpopulations

African (AFR)

AF:

0.236

AC:

2262

AN:

9574

American (AMR)

AF:

0.506

AC:

7460

AN:

14750

Ashkenazi Jewish (ASJ)

AF:

0.616

AC:

5885

AN:

9546

East Asian (EAS)

AF:

0.267

AC:

4931

AN:

18450

South Asian (SAS)

AF:

0.371

AC:

15493

AN:

41732

European-Finnish (FIN)

AF:

0.400

AC:

6926

AN:

17332

Middle Eastern (MID)

AF:

0.463

AC:

659

AN:

1422

European-Non Finnish (NFE)

AF:

0.407

AC:

75650

AN:

185950

Other (OTH)

AF:

0.399

AC:

7369

AN:

18468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

2731

5463

8194

10926

13657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

434

868

1302

1736

2170

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.154

AC:

281

AN:

1830

Hom.:

Cov.:

AF XY:

0.160

AC XY:

143

AN XY:

894

show subpopulations

African (AFR)

AF:

0.0869

AC:

AN:

518

American (AMR)

AF:

0.217

AC:

AN:

272

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

AN:

East Asian (EAS)

AF:

0.0946

AC:

AN:

222

South Asian (SAS)

AF:

0.201

AC:

AN:

244

European-Finnish (FIN)

AF:

0.250

AC:

AN:

Middle Eastern (MID)

AF:

0.0556

AC:

AN:

European-Non Finnish (NFE)

AF:

0.190

AC:

AN:

478

Other (OTH)

AF:

0.132

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.344

Hom.:

909

ExAC

AF:

0.0444

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0030

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.0078

LIST_S2

Benign

0.070

MetaRNN

Benign

0.0000089

MetaSVM

Benign

-0.99

PhyloP100

0.35

PrimateAI

Benign

0.46

PROVEAN

Benign

1.8

REVEL

Benign

0.055

Sift

Benign

0.29

Sift4G

Benign

0.98

Vest4

0.032

MPC

0.35

ClinPred

0.0030

GERP RS

2.9

Varity_R

0.040

gMVP

0.12

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

Other links and lift over