rs41270458

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001365276.2(TNXB):c.1734C>T(p.Asp578Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,604,102 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 36 hom., cov: 34)

Exomes 𝑓: 0.022 ( 408 hom. )

Consequence

TNXB
NM_001365276.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.78

Publications

8 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=-0.85).

BP6

Variant 6-32096119-G-A is Benign according to our data. Variant chr6-32096119-G-A is described in ClinVar as Benign. ClinVar VariationId is 261126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.78 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2782/151800) while in subpopulation NFE AF = 0.0255 (1730/67866). AF 95% confidence interval is 0.0245. There are 36 homozygotes in GnomAd4. There are 1374 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.1734C>T	p.Asp578Asp	synonymous_variant	Exon 3 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.1734C>T	p.Asp578Asp	synonymous_variant	Exon 3 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.1734C>T	p.Asp578Asp	synonymous_variant	Exon 3 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.1734C>T	p.Asp578Asp	synonymous_variant	Exon 3 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2783

AN:

151680

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00366

Gnomad AMI

AF:

0.00444

Gnomad AMR

AF:

0.0216

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.00390

Gnomad SAS

AF:

0.0214

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.0132

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0264

GnomAD2 exomes

AF:

0.0222

AC:

4974

AN:

224438

AF XY:

0.0236

show subpopulations

Gnomad AFR exome

AF:

0.00365

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.00856

Gnomad EAS exome

AF:

0.00463

Gnomad FIN exome

AF:

0.0345

Gnomad NFE exome

AF:

0.0278

Gnomad OTH exome

AF:

0.0210

GnomAD4 exome

AF:

0.0221

AC:

32079

AN:

1452302

Hom.:

408

Cov.:

AF XY:

0.0225

AC XY:

16242

AN XY:

721586

show subpopulations

African (AFR)

AF:

0.00292

AC:

AN:

33242

American (AMR)

AF:

0.0149

AC:

646

AN:

43426

Ashkenazi Jewish (ASJ)

AF:

0.00798

AC:

206

AN:

25804

East Asian (EAS)

AF:

0.00494

AC:

194

AN:

39264

South Asian (SAS)

AF:

0.0253

AC:

2137

AN:

84506

European-Finnish (FIN)

AF:

0.0347

AC:

1791

AN:

51624

Middle Eastern (MID)

AF:

0.0135

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0232

AC:

25672

AN:

1108614

Other (OTH)

AF:

0.0209

AC:

1258

AN:

60064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2650

5301

7951

10602

13252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

892

1784

2676

3568

4460

<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:

0.0183

AC:

2782

AN:

151800

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1374

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.00364

AC:

151

AN:

41430

American (AMR)

AF:

0.0216

AC:

329

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

AN:

3468

East Asian (EAS)

AF:

0.00392

AC:

AN:

5108

South Asian (SAS)

AF:

0.0213

AC:

102

AN:

4798

European-Finnish (FIN)

AF:

0.0334

AC:

353

AN:

10576

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0255

AC:

1730

AN:

67866

Other (OTH)

AF:

0.0261

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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

108

144

180

<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:

0.0229

Hom.:

111

Bravo

AF:

0.0163

Asia WGS

AF:

0.00808

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Ehlers-Danlos syndrome

Benign:1

Jun 23, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 15, 2019

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

-0.85

CADD

Benign

0.80

(source)

DANN

Benign

0.80

PhyloP100

-3.8

Mutation Taster

=98/2

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

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