6-32049396-G-C

Variant names:

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.9631C>G(p.Arg3211Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 1,612,554 control chromosomes in the GnomAD database, including 1,923 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3211H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.038 ( 221 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1702 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.41

Publications

7 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=0.0019940138).

BP6

Variant 6-32049396-G-C is Benign according to our data. Variant chr6-32049396-G-C is described in ClinVar as Benign. ClinVar VariationId is 261179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0376 (5725/152236) while in subpopulation NFE AF = 0.0463 (3150/68008). AF 95% confidence interval is 0.045. There are 221 homozygotes in GnomAd4. There are 3072 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 221 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.9631C>G	p.Arg3211Gly	missense_variant	Exon 28 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.10372C>G	p.Arg3458Gly	missense_variant	Exon 29 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.9625C>G	p.Arg3209Gly	missense_variant	Exon 28 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.9631C>G	p.Arg3211Gly	missense_variant	Exon 28 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.10372C>G	p.Arg3458Gly	missense_variant	Exon 29 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.9631C>G	p.Arg3211Gly	missense_variant	Exon 28 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

5724

AN:

152118

Hom.:

221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00729

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.0189

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0463

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0390

AC:

9626

AN:

246914

AF XY:

0.0392

show subpopulations

Gnomad AFR exome

AF:

0.00790

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.00530

Gnomad EAS exome

AF:

0.00178

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.0458

Gnomad OTH exome

AF:

0.0390

GnomAD4 exome

AF:

0.0413

AC:

60306

AN:

1460318

Hom.:

1702

Cov.:

AF XY:

0.0406

AC XY:

29515

AN XY:

726464

show subpopulations

African (AFR)

AF:

0.00586

AC:

196

AN:

33444

American (AMR)

AF:

0.0162

AC:

726

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00520

AC:

136

AN:

26130

East Asian (EAS)

AF:

0.00136

AC:

AN:

39700

South Asian (SAS)

AF:

0.0154

AC:

1328

AN:

86204

European-Finnish (FIN)

AF:

0.140

AC:

7443

AN:

53284

Middle Eastern (MID)

AF:

0.0286

AC:

135

AN:

4718

European-Non Finnish (NFE)

AF:

0.0435

AC:

48354

AN:

1111856

Other (OTH)

AF:

0.0321

AC:

1934

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

4704

9408

14111

18815

23519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1762

3524

5286

7048

8810

<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:

0.0376

AC:

5725

AN:

152236

Hom.:

221

Cov.:

AF XY:

0.0413

AC XY:

3072

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00727

AC:

302

AN:

41542

American (AMR)

AF:

0.0229

AC:

350

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00406

AC:

AN:

5178

South Asian (SAS)

AF:

0.0195

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.156

AC:

1649

AN:

10586

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0463

AC:

3150

AN:

68008

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

278

555

833

1110

1388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0310

Hom.:

Bravo

AF:

0.0263

TwinsUK

AF:

0.0426

AC:

158

ALSPAC

AF:

0.0464

AC:

179

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0467

AC:

238

ExAC

AF:

0.0389

AC:

4697

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0440

EpiControl

AF:

0.0415

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

Jul 05, 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

Jul 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 24, 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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

T;.;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.90

.;D;D;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

1.4

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.9

.;.;D;.

REVEL

Benign

0.23

Sift

Benign

0.39

.;.;T;.

Sift4G

Uncertain

0.015

.;.;D;D

Vest4

0.21

ClinPred

0.041

GERP RS

4.4

Varity_R

0.29

Mutation Taster

=99/1

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

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