6-32042349-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001365276.2(TNXB):c.12224G>A(p.Arg4075His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4075C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0068 ( 1 hom., cov: 19)

Exomes 𝑓: 0.045 ( 6 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.08

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005153835).

BP6

Variant 6-32042349-C-T is Benign according to our data. Variant chr6-32042349-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.12224G>A	p.Arg4075His	missense_variant	Exon 41 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.12965G>A	p.Arg4322His	missense_variant	Exon 42 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.12218G>A	p.Arg4073His	missense_variant	Exon 41 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681
TNXB	NM_032470.4 link	c.1511G>A	p.Arg504His	missense_variant	Exon 10 of 13		NP_115859.2	P22105-2Q6IPK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.12224G>A	p.Arg4075His	missense_variant	Exon 41 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

848

AN:

124242

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00120

Gnomad AMR

AF:

0.00474

Gnomad ASJ

AF:

0.00129

Gnomad EAS

AF:

0.00705

Gnomad SAS

AF:

0.0136

Gnomad FIN

AF:

0.00403

Gnomad MID

AF:

0.0149

Gnomad NFE

AF:

0.00387

Gnomad OTH

AF:

0.00646

GnomAD3 exomes

AF:

0.0317

AC:

6690

AN:

210924

Hom.:

AF XY:

0.0355

AC XY:

4052

AN XY:

114162

show subpopulations

Gnomad AFR exome

AF:

0.0688

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.0269

Gnomad SAS exome

AF:

0.0827

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0266

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0445

AC:

55050

AN:

1236720

Hom.:

Cov.:

AF XY:

0.0430

AC XY:

26655

AN XY:

619428

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.0179

Gnomad4 ASJ exome

AF:

0.0215

Gnomad4 EAS exome

AF:

0.0194

Gnomad4 SAS exome

AF:

0.0609

Gnomad4 FIN exome

AF:

0.00695

Gnomad4 NFE exome

AF:

0.0463

Gnomad4 OTH exome

AF:

0.0430

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00684

AC:

850

AN:

124342

Hom.:

Cov.:

AF XY:

0.00681

AC XY:

413

AN XY:

60682

show subpopulations

Gnomad4 AFR

AF:

0.0150

Gnomad4 AMR

AF:

0.00474

Gnomad4 ASJ

AF:

0.00129

Gnomad4 EAS

AF:

0.00730

Gnomad4 SAS

AF:

0.0130

Gnomad4 FIN

AF:

0.00403

Gnomad4 NFE

AF:

0.00387

Gnomad4 OTH

AF:

0.00637

Alfa

AF:

0.0163

Hom.:

ExAC

AF:

0.0869

AC:

10532

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2015

Pediatric Services, National Institutes of Health, Clinical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Uncertain:1Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

May 21, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;.;.;.;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

.;T;T;D;D

MetaRNN

Benign

0.0052

T;T;T;T;T

MetaSVM

Pathogenic

0.89

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.4

.;.;D;D;.

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

.;.;D;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D;D

Vest4

0.21, 0.72

MPC

3.4

ClinPred

0.072

GERP RS

4.8

Varity_R

0.67

gMVP

0.92

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

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