rs9267795

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.9641G>T(p.Gly3214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,612,534 control chromosomes in the GnomAD database, including 402 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. G3214R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 86 hom., cov: 32)

Exomes 𝑓: 0.016 ( 316 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.25

Publications

12 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=0.0028644204).

BP6

Variant 6-32049386-C-A is Benign according to our data. Variant chr6-32049386-C-A is described in ClinVar as Benign. ClinVar VariationId is 261180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0245 (3733/152254) while in subpopulation AFR AF = 0.0444 (1846/41534). AF 95% confidence interval is 0.0428. There are 86 homozygotes in GnomAd4. There are 1794 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 86 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.9641G>T	p.Gly3214Val	missense_variant	Exon 28 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.10382G>T	p.Gly3461Val	missense_variant	Exon 29 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.9635G>T	p.Gly3212Val	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.9641G>T	p.Gly3214Val	missense_variant	Exon 28 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.10382G>T	p.Gly3461Val	missense_variant	Exon 29 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.9641G>T	p.Gly3214Val	missense_variant	Exon 28 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3730

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0446

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.0433

Gnomad SAS

AF:

0.0223

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0202

AC:

4993

AN:

247122

AF XY:

0.0201

show subpopulations

Gnomad AFR exome

AF:

0.0443

Gnomad AMR exome

AF:

0.0216

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.0597

Gnomad FIN exome

AF:

0.00283

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0158

AC:

23060

AN:

1460280

Hom.:

316

Cov.:

AF XY:

0.0160

AC XY:

11599

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.0438

AC:

1464

AN:

33440

American (AMR)

AF:

0.0223

AC:

999

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

309

AN:

26130

East Asian (EAS)

AF:

0.0244

AC:

967

AN:

39700

South Asian (SAS)

AF:

0.0276

AC:

2377

AN:

86190

European-Finnish (FIN)

AF:

0.00347

AC:

185

AN:

53320

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

4670

European-Non Finnish (NFE)

AF:

0.0141

AC:

15678

AN:

1111860

Other (OTH)

AF:

0.0167

AC:

1004

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1854

3708

5563

7417

9271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.0245

AC:

3733

AN:

152254

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

1794

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0444

AC:

1846

AN:

41534

American (AMR)

AF:

0.0297

AC:

455

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3468

East Asian (EAS)

AF:

0.0436

AC:

225

AN:

5164

South Asian (SAS)

AF:

0.0226

AC:

109

AN:

4832

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0140

AC:

950

AN:

68012

Other (OTH)

AF:

0.0345

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

175

351

526

702

877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.0124

Hom.:

Bravo

AF:

0.0271

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.0408

AC:

105

ESP6500EA

AF:

0.0169

AC:

ExAC

AF:

0.0202

AC:

2440

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0152

EpiControl

AF:

0.0160

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 02, 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 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 18, 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

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.12

.;.;.;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.62

.;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T

MetaSVM

Benign

-0.86

PhyloP100

1.2

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.0

.;.;D;.

REVEL

Benign

0.18

Sift

Uncertain

0.023

.;.;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D

Vest4

0.19

ClinPred

0.040

GERP RS

3.5

Varity_R

0.45

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over