rs1150752

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001365276.2(TNXB):c.904A>G(p.Thr302Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,611,064 control chromosomes in the GnomAD database, including 9,877 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.062 ( 457 hom., cov: 33)

Exomes 𝑓: 0.10 ( 9420 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.174

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038123429).

BP6

Variant 6-32096949-T-C is Benign according to our data. Variant chr6-32096949-T-C is described in ClinVar as [Benign]. Clinvar id is 261174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32096949-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.904A>G	p.Thr302Ala	missense_variant	3/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.904A>G	p.Thr302Ala	missense_variant	3/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.904A>G	p.Thr302Ala	missense_variant	3/44		NM_001365276.2	ENSP00000496448		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0624

AC:

9413

AN:

150772

Hom.:

457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0710

Gnomad AMR

AF:

0.0292

Gnomad ASJ

AF:

0.0388

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0806

Gnomad MID

AF:

0.0195

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.0470

GnomAD3 exomes

AF:

0.0589

AC:

14500

AN:

246382

Hom.:

748

AF XY:

0.0579

AC XY:

7752

AN XY:

133788

show subpopulations

Gnomad AFR exome

AF:

0.0141

Gnomad AMR exome

AF:

0.0215

Gnomad ASJ exome

AF:

0.0369

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.0000660

Gnomad FIN exome

AF:

0.0779

Gnomad NFE exome

AF:

0.100

Gnomad OTH exome

AF:

0.0600

GnomAD4 exome

AF:

0.101

AC:

147319

AN:

1460176

Hom.:

9420

Cov.:

AF XY:

0.0975

AC XY:

70835

AN XY:

726260

show subpopulations

Gnomad4 AFR exome

AF:

0.0140

Gnomad4 AMR exome

AF:

0.0221

Gnomad4 ASJ exome

AF:

0.0400

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0808

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.0864

GnomAD4 genome

AF:

0.0624

AC:

9410

AN:

150888

Hom.:

457

Cov.:

AF XY:

0.0579

AC XY:

4273

AN XY:

73744

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.0291

Gnomad4 ASJ

AF:

0.0388

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0806

Gnomad4 NFE

AF:

0.106

Gnomad4 OTH

AF:

0.0466

Alfa

AF:

0.0780

Hom.:

448

Bravo

AF:

0.0567

TwinsUK

AF:

0.129

AC:

480

ALSPAC

AF:

0.129

AC:

497

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.106

AC:

900

ExAC

AF:

0.0589

AC:

7141

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2018

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

0.075

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.4

DANN

Benign

0.61

DEOGEN2

Benign

0.071

T;.;T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.22

.;T;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.6

.;.;N;.;D

REVEL

Benign

0.037

Sift

Benign

0.067

.;.;T;.;T

Sift4G

Benign

0.094

.;.;T;T;T

Vest4

0.040, 0.082

ClinPred

0.0062

GERP RS

-2.2

Varity_R

0.086

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