NM_001365276.2:c.7251A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001365276.2(TNXB):c.7251A>G(p.Leu2417Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,612,278 control chromosomes in the GnomAD database, including 248,315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23052 hom., cov: 30)

Exomes 𝑓: 0.55 ( 225263 hom. )

Consequence

TNXB
NM_001365276.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.472

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 6-32061638-T-C is Benign according to our data. Variant chr6-32061638-T-C is described in ClinVar as [Benign]. Clinvar id is 261156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.472 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.7251A>G	p.Leu2417Leu	synonymous_variant	Exon 21 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.7992A>G	p.Leu2664Leu	synonymous_variant	Exon 22 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.7251A>G	p.Leu2417Leu	synonymous_variant	Exon 21 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.7251A>G	p.Leu2417Leu	synonymous_variant	Exon 21 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.7992A>G	p.Leu2664Leu	synonymous_variant	Exon 22 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.7251A>G	p.Leu2417Leu	synonymous_variant	Exon 21 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.546

AC:

82731

AN:

151648

Hom.:

23040

Cov.:

show subpopulations

Gnomad AFR

AF:

0.472

Gnomad AMI

AF:

0.632

Gnomad AMR

AF:

0.625

Gnomad ASJ

AF:

0.683

Gnomad EAS

AF:

0.617

Gnomad SAS

AF:

0.718

Gnomad FIN

AF:

0.563

Gnomad MID

AF:

0.706

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.576

GnomAD2 exomes

AF:

0.601

AC:

147134

AN:

244634

AF XY:

0.610

show subpopulations

Gnomad AFR exome

AF:

0.471

Gnomad AMR exome

AF:

0.678

Gnomad ASJ exome

AF:

0.686

Gnomad EAS exome

AF:

0.601

Gnomad FIN exome

AF:

0.557

Gnomad NFE exome

AF:

0.554

Gnomad OTH exome

AF:

0.585

GnomAD4 exome

AF:

0.550

AC:

802625

AN:

1460512

Hom.:

225263

Cov.:

AF XY:

0.557

AC XY:

404837

AN XY:

726532

show subpopulations

African (AFR)

AF:

0.483

AC:

16158

AN:

33470

American (AMR)

AF:

0.673

AC:

30108

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.679

AC:

17736

AN:

26132

East Asian (EAS)

AF:

0.636

AC:

25236

AN:

39700

South Asian (SAS)

AF:

0.748

AC:

64500

AN:

86248

European-Finnish (FIN)

AF:

0.553

AC:

28956

AN:

52338

Middle Eastern (MID)

AF:

0.691

AC:

3967

AN:

5740

European-Non Finnish (NFE)

AF:

0.524

AC:

582258

AN:

1111814

Other (OTH)

AF:

0.559

AC:

33706

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

24354

48708

73063

97417

121771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16600

33200

49800

66400

83000

<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:

0.546

AC:

82790

AN:

151766

Hom.:

23052

Cov.:

AF XY:

0.554

AC XY:

41069

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.472

AC:

19535

AN:

41344

American (AMR)

AF:

0.625

AC:

9534

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

2370

AN:

3472

East Asian (EAS)

AF:

0.618

AC:

3172

AN:

5134

South Asian (SAS)

AF:

0.717

AC:

3443

AN:

4804

European-Finnish (FIN)

AF:

0.563

AC:

5940

AN:

10560

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.542

AC:

36812

AN:

67886

Other (OTH)

AF:

0.574

AC:

1207

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1856

3712

5568

7424

9280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<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:

0.529

Hom.:

8511

Bravo

AF:

0.545

EpiCase

AF:

0.572

EpiControl

AF:

0.579

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Vesicoureteral reflux 8

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 20, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 04, 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

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.4

(source)

DANN

Benign

0.82

PhyloP100

0.47

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