rs17201602

Positions:

chr6-32095904-C-T

Variant summary

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

The NM_001365276.2(TNXB):c.1949G>A(p.Arg650His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 1,612,498 control chromosomes in the GnomAD database, including 3,433 homozygotes. In-silico tool predicts 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R650G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.080 ( 675 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2758 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.57

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=0.0016717613).

BP6

Variant 6-32095904-C-T is Benign according to our data. Variant chr6-32095904-C-T is described in ClinVar as [Benign]. Clinvar id is 261127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32095904-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.1949G>A	p.Arg650His	missense_variant	3/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.1949G>A	p.Arg650His	missense_variant	3/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.1949G>A	p.Arg650His	missense_variant	3/44		NM_001365276.2		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0800

AC:

12179

AN:

152150

Hom.:

676

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0966

Gnomad ASJ

AF:

0.0818

Gnomad EAS

AF:

0.0404

Gnomad SAS

AF:

0.0824

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.0467

Gnomad OTH

AF:

0.109

GnomAD3 exomes

AF:

0.0607

AC:

14485

AN:

238816

Hom.:

646

AF XY:

0.0615

AC XY:

8037

AN XY:

130638

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.0602

Gnomad ASJ exome

AF:

0.0775

Gnomad EAS exome

AF:

0.0459

Gnomad SAS exome

AF:

0.0954

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.0486

Gnomad OTH exome

AF:

0.0722

GnomAD4 exome

AF:

0.0518

AC:

75700

AN:

1460230

Hom.:

2758

Cov.:

AF XY:

0.0530

AC XY:

38468

AN XY:

726366

show subpopulations

Gnomad4 AFR exome

AF:

0.162

Gnomad4 AMR exome

AF:

0.0658

Gnomad4 ASJ exome

AF:

0.0800

Gnomad4 EAS exome

AF:

0.0274

Gnomad4 SAS exome

AF:

0.0966

Gnomad4 FIN exome

AF:

0.0124

Gnomad4 NFE exome

AF:

0.0454

Gnomad4 OTH exome

AF:

0.0619

GnomAD4 genome

AF:

0.0800

AC:

12178

AN:

152268

Hom.:

675

Cov.:

AF XY:

0.0796

AC XY:

5928

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.150

Gnomad4 AMR

AF:

0.0965

Gnomad4 ASJ

AF:

0.0818

Gnomad4 EAS

AF:

0.0405

Gnomad4 SAS

AF:

0.0827

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.0467

Gnomad4 OTH

AF:

0.107

Alfa

AF:

0.0557

Hom.:

386

Bravo

AF:

0.0897

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0488

AC:

188

ESP6500AA

AF:

0.132

AC:

553

ESP6500EA

AF:

0.0481

AC:

405

ExAC

AF:

0.0627

AC:

7575

Asia WGS

AF:

0.0770

AC:

270

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 19, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 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

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;T;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.84

.;T;T;D;D

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.1

.;.;D;.;D

REVEL

Benign

0.11

Sift

Benign

0.055

.;.;T;.;D

Sift4G

Uncertain

0.0030

.;.;D;D;D

Vest4

0.25, 0.23

ClinPred

0.022

GERP RS

4.3

Varity_R

0.29

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