dbSNP rs118086587: TNXB:p.Arg490Gln (chr6-32096384-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365276.2(TNXB):c.1469G>A(p.Arg490Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,560,144 control chromosomes in the GnomAD database, including 148 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R490R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 21 hom., cov: 34)

Exomes 𝑓: 0.0046 ( 127 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.285

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003249526).

BP6

Variant 6-32096384-C-T is Benign according to our data. Variant chr6-32096384-C-T is described in ClinVar as Benign. ClinVar VariationId is 261124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00575 (845/146998) while in subpopulation AMR AF = 0.0323 (478/14800). AF 95% confidence interval is 0.0299. There are 21 homozygotes in GnomAd4. There are 483 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 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.1469G>A	p.Arg490Gln	missense	Exon 3 of 44	NP_001352205.1
TNXB	NM_001428335.1		c.1469G>A	p.Arg490Gln	missense	Exon 3 of 45	NP_001415264.1
TNXB	NM_019105.8		c.1469G>A	p.Arg490Gln	missense	Exon 3 of 44	NP_061978.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TNXB	ENST00000644971.2	MANE Select	c.1469G>A	p.Arg490Gln	missense	Exon 3 of 44	ENSP00000496448.1
TNXB	ENST00000479795.1	TSL:1	c.1469G>A	p.Arg490Gln	missense	Exon 3 of 5	ENSP00000418248.1
TNXB	ENST00000486148.1	TSL:1	n.1864G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00571

AC:

839

AN:

146858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0319

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0219

Gnomad SAS

AF:

0.000433

Gnomad FIN

AF:

0.00699

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00253

Gnomad OTH

AF:

0.00401

GnomAD2 exomes

AF:

0.0115

AC:

2003

AN:

174274

AF XY:

0.00871

show subpopulations

Gnomad AFR exome

AF:

0.000542

Gnomad AMR exome

AF:

0.0529

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0172

Gnomad FIN exome

AF:

0.00783

Gnomad NFE exome

AF:

0.00207

Gnomad OTH exome

AF:

0.00564

GnomAD4 exome

AF:

0.00459

AC:

6493

AN:

1413146

Hom.:

127

Cov.:

AF XY:

0.00423

AC XY:

2965

AN XY:

700216

show subpopulations

African (AFR)

AF:

0.000493

AC:

AN:

32434

American (AMR)

AF:

0.0452

AC:

1776

AN:

39300

Ashkenazi Jewish (ASJ)

AF:

0.0000788

AC:

AN:

25378

East Asian (EAS)

AF:

0.0425

AC:

1592

AN:

37456

South Asian (SAS)

AF:

0.000344

AC:

AN:

81464

European-Finnish (FIN)

AF:

0.00689

AC:

259

AN:

37616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00242

AC:

2652

AN:

1094880

Other (OTH)

AF:

0.00285

AC:

168

AN:

58892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

444

887

1331

1774

2218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00575

AC:

845

AN:

146998

Hom.:

Cov.:

AF XY:

0.00672

AC XY:

483

AN XY:

71882

show subpopulations

African (AFR)

AF:

0.000351

AC:

AN:

39882

American (AMR)

AF:

0.0323

AC:

478

AN:

14800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.0219

AC:

104

AN:

4742

South Asian (SAS)

AF:

0.000434

AC:

AN:

4612

European-Finnish (FIN)

AF:

0.00699

AC:

AN:

10164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.00254

AC:

168

AN:

66266

Other (OTH)

AF:

0.00395

AC:

AN:

2024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00274

Hom.:

Bravo

AF:

0.00686

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.00636

AC:

742

Asia WGS

AF:

0.0100

AC:

AN:

3478

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

Ehlers-Danlos syndrome

Benign:1

Jul 22, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8

Benign:1

Jul 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jul 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Feb 01, 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.069

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.87

PhyloP100

0.28

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.8

REVEL

Benign

0.091

Sift

Benign

0.30

Sift4G

Uncertain

0.034

Vest4

0.26

ClinPred

0.022

GERP RS

2.3

Varity_R

0.082

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over