Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001365276.2(TNXB):c.9672G>A(p.Leu3224Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,612,520 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 9 hom., cov: 33)

Exomes 𝑓: 0.012 ( 154 hom. )

Consequence

TNXB
NM_001365276.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.95

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 6-32049355-C-T is Benign according to our data. Variant chr6-32049355-C-T is described in ClinVar as Benign. ClinVar VariationId is 261181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.95 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1590/152328) while in subpopulation AFR AF = 0.0144 (597/41572). AF 95% confidence interval is 0.0134. There are 9 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. 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.9672G>A	p.Leu3224Leu	synonymous	Exon 28 of 44	NP_001352205.1
TNXB	NM_001428335.1		c.10413G>A	p.Leu3471Leu	synonymous	Exon 29 of 45	NP_001415264.1
TNXB	NM_019105.8		c.9666G>A	p.Leu3222Leu	synonymous	Exon 28 of 44	NP_061978.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNXB	ENST00000644971.2	MANE Select	c.9672G>A	p.Leu3224Leu	synonymous	Exon 28 of 44	ENSP00000496448.1
TNXB	ENST00000647633.1		c.10413G>A	p.Leu3471Leu	synonymous	Exon 29 of 45	ENSP00000497649.1
TNXB	ENST00000375244.7	TSL:5	c.9672G>A	p.Leu3224Leu	synonymous	Exon 28 of 44	ENSP00000364393.3

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1589

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0116

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.00703

AC:

1737

AN:

247136

AF XY:

0.00686

show subpopulations

Gnomad AFR exome

AF:

0.0135

Gnomad AMR exome

AF:

0.00679

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00914

Gnomad OTH exome

AF:

0.00747

GnomAD4 exome

AF:

0.0116

AC:

16897

AN:

1460192

Hom.:

154

Cov.:

AF XY:

0.0111

AC XY:

8093

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.0131

AC:

437

AN:

33442

American (AMR)

AF:

0.00725

AC:

324

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

587

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.00259

AC:

AN:

4634

European-Non Finnish (NFE)

AF:

0.0132

AC:

14669

AN:

1111848

Other (OTH)

AF:

0.0140

AC:

842

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1146

2293

3439

4586

5732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.0104

AC:

1590

AN:

152328

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

706

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0144

AC:

597

AN:

41572

American (AMR)

AF:

0.00653

AC:

100

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0116

AC:

788

AN:

68012

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0115

Hom.:

Bravo

AF:

0.0111

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

2.0

(source)

DANN

Benign

0.64

PhyloP100

3.0

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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.

NM_001365276.2:c.9672G>A

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over