6-32042485-G-C

Position:

chr6-32042485-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001365276.2(TNXB):c.12180C>G(p.Cys4060Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000018 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: -0.883

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNXB	NM_001365276.2 linkuse as main transcript	c.12180C>G	p.Cys4060Trp	missense_variant	40/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.12174C>G	p.Cys4058Trp	missense_variant	40/44		NP_061978.6
TNXB	NM_032470.4 linkuse as main transcript	c.1467C>G	p.Cys489Trp	missense_variant	9/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.12180C>G	p.Cys4060Trp	missense_variant	40/44		NM_001365276.2	ENSP00000496448		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250654

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135660

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000185

AC:

AN:

1460834

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151870

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74202

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000612

Hom.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 12, 2024	PM1, PS4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified previously in conjunction with a fusion event involving TNXB and TNXA in individuals with a phenotype of congenital adrenal hyperplasia and hypermobile Ehlers-Danlos syndrome (Morissette et al., 2015; Demirdas et al., 2017); This variant is associated with the following publications: (PMID: 26075496, 31141158, 32572181, 31229653, 27582382) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TNXB: PP3 -

Ehlers-Danlos syndrome due to tenascin-X deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Pediatric Services, National Institutes of Health, Clinical Center

Jan 01, 2015

- -

TNXB-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The TNXB c.12174C>G variant is predicted to result in the amino acid substitution p.Cys4058Trp. This variant is reported in 0.0055% of alleles in individuals of European descent in gnomAD, however this variant falls within a highly paralogous region and allele frequency data should be interpreted with caution. Likely originated from the pseudogene TNXA, this variant has been reported in TNXB exon 40 by itself or with the pseudogene-derived 120bp deletion spanning exon 35/intron 35 due to a rearrangement event (unequal crossover or gene conversion). Located closer to the CYP21A2 gene (which is in tandem 3’ to 3’ with TNXB) in the RCCX locus, this variant alone (i.e. not with the 120bp deletion) can represent a different chimera TNXA/TNXB gene (Morissette et al. 2015. PubMed ID: 26075496; Chen et al. 2016. PubMed ID: 27297501; Miller and Merke. 2018. PubMed ID: 29734195). These studies suggest that this variant could be pathogenic. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.37

.;.;.;.;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.79

.;T;T;T;T

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.5

.;.;D;D;.

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Pathogenic

0.0

.;.;D;D;D

Vest4

0.82, 0.88

MVP

0.46

MPC

1.3

ClinPred

1.0

GERP RS

-2.4

Varity_R

0.89

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over