rs201397168

Positions:

chr6-32068536-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001365276.2(TNXB):c.6074A>T(p.Asp2025Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0005 in 1,613,814 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 7 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3

Conservation

PhyloP100: 2.73

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011256754).

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.6074A>T	p.Asp2025Val	missense_variant	17/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.6074A>T	p.Asp2025Val	missense_variant	17/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.6074A>T	p.Asp2025Val	missense_variant	17/44		NM_001365276.2		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.6815A>T	p.Asp2272Val	missense_variant	18/45			P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.6074A>T	p.Asp2025Val	missense_variant	17/44	5			P22105-3

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000923

AC:

230

AN:

249130

Hom.:

AF XY:

0.000880

AC XY:

119

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000266

Gnomad OTH exome

AF:

0.000992

GnomAD4 exome

AF:

0.000496

AC:

725

AN:

1461632

Hom.:

Cov.:

AF XY:

0.000529

AC XY:

385

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.0175

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.000539

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.000570

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000957

AC:

ExAC

AF:

0.000711

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 3

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_019105.6:c.6074A>T in the TNXB gene has an allele frequency of 0.018 in Ashkenazi Jewish subpopulation in the gnomAD database. Pathogenic computational verdict because pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationTaster and SIFT. It has been detected in heterozygous state in one individual with Ehlers-Danlos syndrome (PMID: 25326637). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3; PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Feb 05, 2013	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	Reported as a single heterozygous variant in association with joint pain, hypermobility, chronic muscle weakness, and Raynaud's phenomenon (Lee et al., 2014; Kaufman et al., 2016); however no segregation data is available, and at least one patient is Ashkenazi Jewish; This variant is associated with the following publications: (PMID: 31589614, 26582918, 25326637, 28344932) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	TNXB: BP4, BS2 -

Ehlers-Danlos syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2019

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

0.31

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.23

T;.;T

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.56

M_CAP

Benign

0.022

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

-0.26

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.40

Vest4

0.83

MVP

0.59

ClinPred

0.82

GERP RS

5.3

Varity_R

0.44

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

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