NM_001365276.2:c.7440T>C

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.7440T>C(p.Tyr2480Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 1,612,076 control chromosomes in the GnomAD database, including 379,169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.64 ( 31805 hom., cov: 31)

Exomes 𝑓: 0.69 ( 347364 hom. )

Consequence

TNXB
NM_001365276.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.50

Publications

25 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=-0.75).

BP6

Variant 6-32061449-A-G is Benign according to our data. Variant chr6-32061449-A-G is described in ClinVar as Benign. ClinVar VariationId is 261159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.7440T>C	p.Tyr2480Tyr	synonymous_variant	Exon 21 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.8181T>C	p.Tyr2727Tyr	synonymous_variant	Exon 22 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.7440T>C	p.Tyr2480Tyr	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.7440T>C	p.Tyr2480Tyr	synonymous_variant	Exon 21 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.8181T>C	p.Tyr2727Tyr	synonymous_variant	Exon 22 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.7440T>C	p.Tyr2480Tyr	synonymous_variant	Exon 21 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.641

AC:

96871

AN:

151032

Hom.:

31788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.518

Gnomad AMI

AF:

0.716

Gnomad AMR

AF:

0.677

Gnomad ASJ

AF:

0.737

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.747

Gnomad FIN

AF:

0.672

Gnomad MID

AF:

0.748

Gnomad NFE

AF:

0.689

Gnomad OTH

AF:

0.646

GnomAD2 exomes

AF:

0.691

AC:

170335

AN:

246578

AF XY:

0.699

show subpopulations

Gnomad AFR exome

AF:

0.504

Gnomad AMR exome

AF:

0.719

Gnomad ASJ exome

AF:

0.739

Gnomad EAS exome

AF:

0.617

Gnomad FIN exome

AF:

0.668

Gnomad NFE exome

AF:

0.694

Gnomad OTH exome

AF:

0.675

GnomAD4 exome

AF:

0.687

AC:

1004151

AN:

1460928

Hom.:

347364

Cov.:

118

AF XY:

0.692

AC XY:

502599

AN XY:

726812

show subpopulations

African (AFR)

AF:

0.528

AC:

17492

AN:

33132

American (AMR)

AF:

0.715

AC:

31970

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.736

AC:

19233

AN:

26118

East Asian (EAS)

AF:

0.654

AC:

25970

AN:

39700

South Asian (SAS)

AF:

0.776

AC:

66907

AN:

86250

European-Finnish (FIN)

AF:

0.668

AC:

35476

AN:

53138

Middle Eastern (MID)

AF:

0.719

AC:

4145

AN:

5766

European-Non Finnish (NFE)

AF:

0.685

AC:

762070

AN:

1111778

Other (OTH)

AF:

0.678

AC:

40888

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

23691

47381

71072

94762

118453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19402

38804

58206

77608

97010

<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:

0.641

AC:

96935

AN:

151148

Hom.:

31805

Cov.:

AF XY:

0.644

AC XY:

47616

AN XY:

73902

show subpopulations

African (AFR)

AF:

0.518

AC:

21051

AN:

40606

American (AMR)

AF:

0.678

AC:

10354

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.737

AC:

2549

AN:

3460

East Asian (EAS)

AF:

0.633

AC:

3267

AN:

5158

South Asian (SAS)

AF:

0.745

AC:

3590

AN:

4818

European-Finnish (FIN)

AF:

0.672

AC:

7105

AN:

10574

Middle Eastern (MID)

AF:

0.729

AC:

213

AN:

292

European-Non Finnish (NFE)

AF:

0.689

AC:

46803

AN:

67946

Other (OTH)

AF:

0.643

AC:

1350

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1746

3492

5239

6985

8731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.671

Hom.:

14880

Bravo

AF:

0.632

Asia WGS

AF:

0.689

AC:

2397

AN:

3478

EpiCase

AF:

0.703

EpiControl

AF:

0.702

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 19, 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

-0.75

CADD

Benign

0.041

(source)

DANN

Benign

0.58

PhyloP100

-3.5

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