6-32052940-G-T

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.8845C>A(p.Pro2949Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,612,740 control chromosomes in the GnomAD database, including 313 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2949S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 32)

Exomes 𝑓: 0.011 ( 278 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.12

Publications

6 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=0.0022907555).

BP6

Variant 6-32052940-G-T is Benign according to our data. Variant chr6-32052940-G-T is described in ClinVar as Benign. ClinVar VariationId is 261172.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 = 0.0129 (1967/152278) while in subpopulation AMR AF = 0.0361 (552/15298). AF 95% confidence interval is 0.0336. There are 35 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.8845C>A	p.Pro2949Thr	missense_variant	Exon 26 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.9586C>A	p.Pro3196Thr	missense_variant	Exon 27 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.8839C>A	p.Pro2947Thr	missense_variant	Exon 26 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TNXB	ENST00000644971.2 link	c.8845C>A	p.Pro2949Thr	missense_variant	Exon 26 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1 link	c.9586C>A	p.Pro3196Thr	missense_variant	Exon 27 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7 link	c.8845C>A	p.Pro2949Thr	missense_variant	Exon 26 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1964

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0361

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0359

GnomAD2 exomes

AF:

0.0160

AC:

3879

AN:

242894

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00611

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0112

AC:

16417

AN:

1460462

Hom.:

278

Cov.:

AF XY:

0.0110

AC XY:

8021

AN XY:

726534

show subpopulations

African (AFR)

AF:

0.00675

AC:

226

AN:

33480

American (AMR)

AF:

0.0363

AC:

1624

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0970

AC:

2535

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00176

AC:

152

AN:

86254

European-Finnish (FIN)

AF:

0.00147

AC:

AN:

52228

Middle Eastern (MID)

AF:

0.0292

AC:

168

AN:

5760

European-Non Finnish (NFE)

AF:

0.00943

AC:

10489

AN:

1111830

Other (OTH)

AF:

0.0189

AC:

1140

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1071

2142

3212

4283

5354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

424

848

1272

1696

2120

<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:

0.0129

AC:

1967

AN:

152278

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

886

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00580

AC:

241

AN:

41560

American (AMR)

AF:

0.0361

AC:

552

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

727

AN:

68000

Other (OTH)

AF:

0.0355

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

187

281

374

468

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:

0.0137

Hom.:

Bravo

AF:

0.0166

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00434

AC:

ESP6500EA

AF:

0.0126

AC:

ExAC

AF:

0.0135

AC:

1587

EpiCase

AF:

0.0149

EpiControl

AF:

0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Ehlers-Danlos syndrome

Benign:1

Apr 28, 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

Oct 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Feb 12, 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

Benign

0.060

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.0

.;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

.;.;D;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Pathogenic

0.0

.;.;D;D

Vest4

0.0

ClinPred

0.034

GERP RS

1.5

Varity_R

0.069

Mutation Taster

=100/0

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