chr6-32053637-C-T

Position:

chr6-32053637-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365276.2(TNXB):c.8542G>A(p.Gly2848Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,382 control chromosomes in the GnomAD database, including 962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 142 hom., cov: 31)

Exomes 𝑓: 0.023 ( 820 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.52

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=0.0023582876).

BP6

Variant 6-32053637-C-T is Benign according to our data. Variant chr6-32053637-C-T is described in ClinVar as [Benign]. Clinvar id is 261169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32053637-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0243 (3699/152204) while in subpopulation NFE AF= 0.0246 (1675/67996). AF 95% confidence interval is 0.0237. There are 142 homozygotes in gnomad4. There are 2145 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 142 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.8542G>A	p.Gly2848Arg	missense_variant	25/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.8536G>A	p.Gly2846Arg	missense_variant	25/44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.8542G>A	p.Gly2848Arg	missense_variant	25/44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.9283G>A	p.Gly3095Arg	missense_variant	26/45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 linkuse as main transcript	c.8542G>A	p.Gly2848Arg	missense_variant	25/44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3698

AN:

152086

Hom.:

142

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.0855

Gnomad AMR

AF:

0.0100

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.147

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.00863

GnomAD3 exomes

AF:

0.0246

AC:

6047

AN:

245848

Hom.:

231

AF XY:

0.0240

AC XY:

3220

AN XY:

134082

show subpopulations

Gnomad AFR exome

AF:

0.00403

Gnomad AMR exome

AF:

0.00519

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.000223

Gnomad SAS exome

AF:

0.00490

Gnomad FIN exome

AF:

0.135

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0203

GnomAD4 exome

AF:

0.0229

AC:

33428

AN:

1461178

Hom.:

820

Cov.:

AF XY:

0.0223

AC XY:

16194

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00293

Gnomad4 AMR exome

AF:

0.00546

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00632

Gnomad4 FIN exome

AF:

0.129

Gnomad4 NFE exome

AF:

0.0222

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0243

AC:

3699

AN:

152204

Hom.:

142

Cov.:

AF XY:

0.0288

AC XY:

2145

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.00414

Gnomad4 AMR

AF:

0.0100

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00892

Gnomad4 FIN

AF:

0.147

Gnomad4 NFE

AF:

0.0246

Gnomad4 OTH

AF:

0.00854

Alfa

AF:

0.0138

Hom.:

Bravo

AF:

0.0127

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00762

AC:

ESP6500EA

AF:

0.0242

AC:

125

ExAC

AF:

0.0233

AC:

2808

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0181

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 17, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 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

0.18

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

.;.;.;T

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.87

.;D;T;D

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-0.82

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.6

.;.;D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0060

.;.;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D

Vest4

0.19

ClinPred

0.033

GERP RS

4.4

Varity_R

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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