rs28361051

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.8132T>C(p.Ile2711Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,612,982 control chromosomes in the GnomAD database, including 130 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 15 hom., cov: 32)

Exomes 𝑓: 0.010 ( 115 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.499

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=0.0036107898).

BP6

Variant 6-32056597-A-G is Benign according to our data. Variant chr6-32056597-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261167.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 = 0.0099 (1507/152298) while in subpopulation NFE AF = 0.0124 (844/68014). AF 95% confidence interval is 0.0117. There are 15 homozygotes in GnomAd4. There are 814 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.8132T>C	p.Ile2711Thr	missense_variant	Exon 23 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.8873T>C	p.Ile2958Thr	missense_variant	Exon 24 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.8132T>C	p.Ile2711Thr	missense_variant	Exon 23 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.8132T>C	p.Ile2711Thr	missense_variant	Exon 23 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.8873T>C	p.Ile2958Thr	missense_variant	Exon 24 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.8132T>C	p.Ile2711Thr	missense_variant	Exon 23 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00990

AC:

1507

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0292

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00993

AC:

2436

AN:

245218

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00354

Gnomad ASJ exome

AF:

0.0359

Gnomad EAS exome

AF:

0.000391

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0103

AC:

15105

AN:

1460684

Hom.:

115

Cov.:

AF XY:

0.0105

AC XY:

7595

AN XY:

726618

show subpopulations

African (AFR)

AF:

0.00146

AC:

AN:

33480

American (AMR)

AF:

0.00391

AC:

175

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0342

AC:

893

AN:

26132

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.00502

AC:

433

AN:

86252

European-Finnish (FIN)

AF:

0.0255

AC:

1337

AN:

52470

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0105

AC:

11660

AN:

1111818

Other (OTH)

AF:

0.00861

AC:

520

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1037

2073

3110

4146

5183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.00990

AC:

1507

AN:

152298

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

814

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41566

American (AMR)

AF:

0.00523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0331

AC:

115

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5180

South Asian (SAS)

AF:

0.00559

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0292

AC:

310

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0124

AC:

844

AN:

68014

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

159

239

318

398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0143

Hom.:

Bravo

AF:

0.00739

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00120

AC:

ESP6500EA

AF:

0.00985

AC:

ExAC

AF:

0.00897

AC:

1081

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.00937

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TNXB: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

May 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 17, 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

0.081

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.97

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.066

T;.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.17

.;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.94

PhyloP100

-0.50

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

.;.;N;.

REVEL

Benign

0.027

Sift

Benign

0.29

.;.;T;.

Sift4G

Benign

0.18

.;.;T;T

Vest4

0.031

MVP

0.13

ClinPred

0.0041

GERP RS

2.0

Varity_R

0.086

Mutation Taster

=97/3

polymorphism

(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