rs41258944

Positions:

chr6-32049465-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.9562G>A(p.Val3188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,612,640 control chromosomes in the GnomAD database, including 3,258 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 (★★).

Frequency

Genomes: 𝑓 0.068 ( 416 hom., cov: 32)

Exomes 𝑓: 0.059 ( 2842 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0390

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=0.0017081797).

BP6

Variant 6-32049465-C-T is Benign according to our data. Variant chr6-32049465-C-T is described in ClinVar as [Benign]. Clinvar id is 261178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32049465-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 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.9562G>A	p.Val3188Ile	missense_variant	28/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.9556G>A	p.Val3186Ile	missense_variant	28/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.9562G>A	p.Val3188Ile	missense_variant	28/44		NM_001365276.2	ENSP00000496448		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.10303G>A	p.Val3435Ile	missense_variant	29/45			ENSP00000497649	P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.9562G>A	p.Val3188Ile	missense_variant	28/44	5		ENSP00000364393		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0676

AC:

10283

AN:

152098

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.0362

Gnomad ASJ

AF:

0.0692

Gnomad EAS

AF:

0.00886

Gnomad SAS

AF:

0.0605

Gnomad FIN

AF:

0.0188

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0598

Gnomad OTH

AF:

0.0636

GnomAD3 exomes

AF:

0.0484

AC:

11881

AN:

245582

Hom.:

408

AF XY:

0.0496

AC XY:

6649

AN XY:

133956

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0290

Gnomad ASJ exome

AF:

0.0720

Gnomad EAS exome

AF:

0.00290

Gnomad SAS exome

AF:

0.0568

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.0539

Gnomad OTH exome

AF:

0.0479

GnomAD4 exome

AF:

0.0585

AC:

85459

AN:

1460424

Hom.:

2842

Cov.:

AF XY:

0.0578

AC XY:

42006

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.117

Gnomad4 AMR exome

AF:

0.0317

Gnomad4 ASJ exome

AF:

0.0739

Gnomad4 EAS exome

AF:

0.00224

Gnomad4 SAS exome

AF:

0.0548

Gnomad4 FIN exome

AF:

0.0211

Gnomad4 NFE exome

AF:

0.0613

Gnomad4 OTH exome

AF:

0.0634

GnomAD4 genome

AF:

0.0676

AC:

10291

AN:

152216

Hom.:

416

Cov.:

AF XY:

0.0644

AC XY:

4790

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.111

Gnomad4 AMR

AF:

0.0362

Gnomad4 ASJ

AF:

0.0692

Gnomad4 EAS

AF:

0.00888

Gnomad4 SAS

AF:

0.0599

Gnomad4 FIN

AF:

0.0188

Gnomad4 NFE

AF:

0.0598

Gnomad4 OTH

AF:

0.0630

Alfa

AF:

0.0646

Hom.:

148

Bravo

AF:

0.0714

TwinsUK

AF:

0.0601

AC:

223

ALSPAC

AF:

0.0586

AC:

226

ESP6500AA

AF:

0.113

AC:

283

ESP6500EA

AF:

0.0622

AC:

313

ExAC

AF:

0.0494

AC:

5915

EpiCase

AF:

0.0623

EpiControl

AF:

0.0580

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

Jul 09, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 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

0.084

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

.;.;.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.35

.;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-0.84

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.62

.;.;N;.

REVEL

Benign

0.14

Sift

Benign

0.22

.;.;T;.

Sift4G

Benign

0.21

.;.;T;T

Vest4

0.076

ClinPred

0.0063

GERP RS

3.5

Varity_R

0.028

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