chr6-32069011-C-T

Position:

chr6-32069011-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.5713G>A(p.Glu1905Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,612,862 control chromosomes in the GnomAD database, including 658 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 0.038 ( 170 hom., cov: 32)

Exomes 𝑓: 0.021 ( 488 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0580

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=0.0020450354).

BP6

Variant 6-32069011-C-T is Benign according to our data. Variant chr6-32069011-C-T is described in ClinVar as [Benign]. Clinvar id is 261143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32069011-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 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.5713G>A	p.Glu1905Lys	missense_variant	16/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.5713G>A	p.Glu1905Lys	missense_variant	16/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.5713G>A	p.Glu1905Lys	missense_variant	16/44		NM_001365276.2		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.6454G>A	p.Glu2152Lys	missense_variant	17/45			P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.5713G>A	p.Glu1905Lys	missense_variant	16/44	5			P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0377

AC:

5737

AN:

152178

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0792

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00289

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0489

GnomAD3 exomes

AF:

0.0211

AC:

5148

AN:

244330

Hom.:

117

AF XY:

0.0198

AC XY:

2642

AN XY:

133704

show subpopulations

Gnomad AFR exome

AF:

0.0800

Gnomad AMR exome

AF:

0.0299

Gnomad ASJ exome

AF:

0.0271

Gnomad EAS exome

AF:

0.00112

Gnomad SAS exome

AF:

0.00863

Gnomad FIN exome

AF:

0.00246

Gnomad NFE exome

AF:

0.0198

Gnomad OTH exome

AF:

0.0317

GnomAD4 exome

AF:

0.0207

AC:

30184

AN:

1460566

Hom.:

488

Cov.:

AF XY:

0.0199

AC XY:

14490

AN XY:

726582

show subpopulations

Gnomad4 AFR exome

AF:

0.0871

Gnomad4 AMR exome

AF:

0.0330

Gnomad4 ASJ exome

AF:

0.0283

Gnomad4 EAS exome

AF:

0.000806

Gnomad4 SAS exome

AF:

0.00876

Gnomad4 FIN exome

AF:

0.00319

Gnomad4 NFE exome

AF:

0.0203

Gnomad4 OTH exome

AF:

0.0219

GnomAD4 genome

AF:

0.0377

AC:

5735

AN:

152296

Hom.:

170

Cov.:

AF XY:

0.0364

AC XY:

2711

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0790

Gnomad4 AMR

AF:

0.0490

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.00290

Gnomad4 SAS

AF:

0.00663

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.0207

Gnomad4 OTH

AF:

0.0479

Alfa

AF:

0.0244

Hom.:

104

Bravo

AF:

0.0436

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0228

AC:

ESP6500AA

AF:

0.0659

AC:

178

ESP6500EA

AF:

0.0220

AC:

114

ExAC

AF:

0.0212

AC:

2495

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 02, 2022

- -

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

Jan 21, 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

0.091

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.76

.;T;T

MetaRNN

Benign

0.0020

T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.0

.;.;N

REVEL

Benign

0.12

Sift

Benign

0.17

.;.;T

Sift4G

Uncertain

0.015

.;.;D

Vest4

0.16

ClinPred

0.065

GERP RS

-1.9

Varity_R

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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