6-32049366-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001365276.2(TNXB):c.9661G>A(p.Val3221Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,612,516 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3221F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 151 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.0220

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027631521).

BP6

Variant 6-32049366-C-T is Benign according to our data. Variant chr6-32049366-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209196.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00129 (197/152312) while in subpopulation SAS AF = 0.0371 (179/4826). AF 95% confidence interval is 0.0327. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 151 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.9661G>A	p.Val3221Met	missense_variant	Exon 28 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.10402G>A	p.Val3468Met	missense_variant	Exon 29 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.9655G>A	p.Val3219Met	missense_variant	Exon 28 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TNXB	ENST00000644971.2 link	c.9661G>A	p.Val3221Met	missense_variant	Exon 28 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1 link	c.10402G>A	p.Val3468Met	missense_variant	Exon 29 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7 link	c.9661G>A	p.Val3221Met	missense_variant	Exon 28 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

199

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0375

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00590

AC:

1458

AN:

247064

AF XY:

0.00790

show subpopulations

Gnomad AFR exome

AF:

0.000269

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000430

Gnomad OTH exome

AF:

0.00465

GnomAD4 exome

AF:

0.00276

AC:

4035

AN:

1460204

Hom.:

151

Cov.:

AF XY:

0.00399

AC XY:

2895

AN XY:

726440

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33442

American (AMR)

AF:

0.000112

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0409

AC:

3521

AN:

86186

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.000647

AC:

AN:

4636

European-Non Finnish (NFE)

AF:

0.000246

AC:

273

AN:

1111850

Other (OTH)

AF:

0.00365

AC:

220

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

276

552

829

1105

1381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00129

AC:

197

AN:

152312

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41562

American (AMR)

AF:

0.0000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0371

AC:

179

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000244

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000393

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00643

AC:

776

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNXB: BP4, BS1, BS2 -

May 28, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency

Uncertain:1

Mar 30, 2015

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been found once in our laboratory in trans with another missense variant [R3211G] in a 40-year-old female with a clinical diagnosis of EDS type III, pain, hypermobility, fevers, night sweats, depression, GI problems, and hyperextensibility in her mother (who was negative for this change). This variant has been seen in our laboratory with other rare variants (phase undetermined) in a 2-year-old male [Q3848K] with tall habitus, joint pain and laxity, hyperelasticity, but also in 3 others without related related symptoms. -

See cases

Uncertain:1

Apr 05, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Feb 02, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 19, 2020

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.044

.;.;.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.69

.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.81

PhyloP100

-0.022

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

.;.;N;.

REVEL

Benign

0.12

Sift

Benign

0.033

.;.;D;.

Sift4G

Uncertain

0.0020

.;.;D;D

Vest4

0.35

MVP

0.15

ClinPred

0.022

GERP RS

0.37

Varity_R

0.048

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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