6-32084536-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001365276.2(TNXB):c.3322G>A(p.Val1108Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,608,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:3

Conservation

PhyloP100: 0.652

Publications

11 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:

ENSG00000294466 (HGNC:):

ENSG00000294466 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05631751).

BP6

Variant 6-32084536-C-T is Benign according to our data. Variant chr6-32084536-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 8552.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TNXB	NM_001365276.2 link	c.3322G>A	p.Val1108Met	missense_variant	Exon 8 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.4063G>A	p.Val1355Met	missense_variant	Exon 9 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.3322G>A	p.Val1108Met	missense_variant	Exon 8 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.3322G>A	p.Val1108Met	missense_variant	Exon 8 of 44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000827

AC:

202

AN:

244180

AF XY:

0.000778

show subpopulations

Gnomad AFR exome

AF:

0.0000698

Gnomad AMR exome

AF:

0.000931

Gnomad ASJ exome

AF:

0.00955

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.000583

Gnomad OTH exome

AF:

0.000835

GnomAD4 exome

AF:

0.000704

AC:

1025

AN:

1456536

Hom.:

Cov.:

AF XY:

0.000678

AC XY:

491

AN XY:

724360

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.000962

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

263

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000703

AC:

AN:

85320

European-Finnish (FIN)

AF:

0.0000198

AC:

AN:

50608

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000580

AC:

644

AN:

1110646

Other (OTH)

AF:

0.00101

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.000690

AC:

105

AN:

152256

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41544

American (AMR)

AF:

0.00118

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000647

AC:

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000637

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000979

AC:

ExAC

AF:

0.000685

AC:

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency

Pathogenic:1Uncertain:1

Apr 22, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change is predicted to replace valine with methionine at codon 1108 of the TNXB protein, p.(Val1108Met), also known as p.(Val1195Met). The valine residue is lowly conserved with methionine present in at least two vertebrates (100 vertebrates, UCSC), and is located in the fibronectin type-III 2 domain. There is a small physicochemical difference between valine and methionine. The variant is present in a large population cohort at a frequency of 0.08% (rs121912575, 221/275,544 alleles, 1 homozygote in gnomAD v2.1), with an allele frequency of 1% in the Ashkenazi Jewish population (98/10,232 alleles, 1 homozygote). The variant has been identified heterozygous (with no other TNXB variant detected) in a single hypermobility-type Ehlers-Danlos syndrome case with normal TNX serum levels and a significant increase in elastic fibre length in a skin biopsy (PMID: 15733269). It has also been identified in centenarians (PMID: 25333069). In molecular polypeptide analyses the variant does not alter three dimensional structure and demonstrates mild destabilization effects on the thermodynamic and mechanical stability (PMID: 20853426). The variant has previously been reported as a variant of uncertain significance (LOVD). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. No criteria are met.

Apr 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

not provided

Uncertain:1Benign:1

Sep 01, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15733269, 25333069, 20853426, 27989960)

May 25, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1

not specified

Uncertain:1

Mar 06, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TNXB c.3322G>A (p.Val1108Met; also described as Val1195Met in the literature) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0007 in 1608792 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TNXB causing Ehlers-Danlos syndrome due to tenascin-X deficiency (0.0007 vs 0.0011), allowing no conclusion about variant significance. c.3322G>A has been reported in the literature in at least an individual in heterozygous state affected with hypermobility type EhlersDanlos syndrome (Zweers_2005). This report, however, does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos syndrome due to tenascin-X deficiency. The following publication have been ascertained in the context of this evaluation (PMID: 15733269). ClinVar contains an entry for this variant (Variation ID: 8552). Based on the evidence outlined above, the variant was classified as uncertain significance.

Ehlers-Danlos syndrome

Uncertain:1

Jul 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See cases

Uncertain:1

Nov 04, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4

TNXB-related disorder

Benign:1

Jul 07, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Cardiovascular phenotype

Benign:1

Oct 24, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.0

.;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.056

T;T;T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

0.65

PrimateAI

Benign

0.45

PROVEAN

Benign

0.0

.;.;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Pathogenic

0.0

.;.;D;D

Vest4

0.0

ClinPred

0.086

GERP RS

4.1

Varity_R

0.13

Mutation Taster

=94/6

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