6-32042349-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001365276.2(TNXB):c.12224G>T(p.Arg4075Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,459,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4075H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000023 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08

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: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.12224G>T	p.Arg4075Leu	missense_variant	Exon 41 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.12965G>T	p.Arg4322Leu	missense_variant	Exon 42 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.12218G>T	p.Arg4073Leu	missense_variant	Exon 41 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681
TNXB	NM_032470.4 link	c.1511G>T	p.Arg504Leu	missense_variant	Exon 10 of 13		NP_115859.2	P22105-2Q6IPK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.12224G>T	p.Arg4075Leu	missense_variant	Exon 41 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0000233

AC:

AN:

128656

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000668

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000163

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000284

AC:

AN:

210924

AF XY:

0.0000175

show subpopulations

Gnomad AFR exome

AF:

0.000175

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000420

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1331210

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

666306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28820

American (AMR)

AF:

0.00

AC:

AN:

42612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24560

East Asian (EAS)

AF:

0.00

AC:

AN:

37328

South Asian (SAS)

AF:

0.00

AC:

AN:

81630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.0000169

AC:

AN:

1003788

Other (OTH)

AF:

0.0000181

AC:

AN:

55240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000233

AC:

AN:

128656

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

62706

show subpopulations

African (AFR)

AF:

0.0000668

AC:

AN:

29944

American (AMR)

AF:

0.00

AC:

AN:

13260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3144

East Asian (EAS)

AF:

0.00

AC:

AN:

4522

South Asian (SAS)

AF:

0.00

AC:

AN:

3736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9838

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000163

AC:

AN:

61346

Other (OTH)

AF:

0.00

AC:

AN:

1754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.12218G>T (p.R4073L) alteration is located in exon 41 (coding exon 40) of the TNXB gene. This alteration results from a G to T substitution at nucleotide position 12218, causing the arginine (R) at amino acid position 4073 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;.;.;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

.;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.86

D;D;D;D;D

MetaSVM

Pathogenic

0.97

PhyloP100

3.1

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.8

.;.;D;D;.

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D;D

Vest4

0.68, 0.84

MVP

0.74

MPC

3.4

ClinPred

1.0

GERP RS

4.8

Varity_R

0.73

gMVP

0.95

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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