rs61995676

Positions:

chr6-32084667-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.3191G>A(p.Arg1064His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,591,792 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 27 hom., cov: 32)

Exomes 𝑓: 0.015 ( 224 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.00200

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=0.0064964592).

BP6

Variant 6-32084667-C-T is Benign according to our data. Variant chr6-32084667-C-T is described in ClinVar as [Benign]. Clinvar id is 261133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32084667-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1926/152304) while in subpopulation NFE AF= 0.0198 (1345/68020). AF 95% confidence interval is 0.0189. There are 27 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.3191G>A	p.Arg1064His	missense_variant	8/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.3191G>A	p.Arg1064His	missense_variant	8/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.3191G>A	p.Arg1064His	missense_variant	8/44		NM_001365276.2	ENSP00000496448		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.3932G>A	p.Arg1311His	missense_variant	9/45			ENSP00000497649	P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.3191G>A	p.Arg1064His	missense_variant	8/44	5		ENSP00000364393		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1926

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0316

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.00764

GnomAD3 exomes

AF:

0.0132

AC:

3126

AN:

236734

Hom.:

AF XY:

0.0131

AC XY:

1691

AN XY:

129554

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.00184

Gnomad ASJ exome

AF:

0.00114

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.000306

Gnomad FIN exome

AF:

0.0298

Gnomad NFE exome

AF:

0.0219

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.0150

AC:

21579

AN:

1439488

Hom.:

224

Cov.:

AF XY:

0.0143

AC XY:

10215

AN XY:

712628

show subpopulations

Gnomad4 AFR exome

AF:

0.00223

Gnomad4 AMR exome

AF:

0.00209

Gnomad4 ASJ exome

AF:

0.00124

Gnomad4 EAS exome

AF:

0.000331

Gnomad4 SAS exome

AF:

0.000357

Gnomad4 FIN exome

AF:

0.0293

Gnomad4 NFE exome

AF:

0.0175

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.0126

AC:

1926

AN:

152304

Hom.:

Cov.:

AF XY:

0.0128

AC XY:

952

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00366

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0316

Gnomad4 NFE

AF:

0.0198

Gnomad4 OTH

AF:

0.00756

Alfa

AF:

0.0165

Hom.:

Bravo

AF:

0.0105

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0195

AC:

ESP6500AA

AF:

0.00416

AC:

ESP6500EA

AF:

0.0154

AC:

ExAC

AF:

0.0147

AC:

1753

Asia WGS

AF:

0.000577

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

Jul 07, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 16, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 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

0.078

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;.;T;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.76

.;T;T;T

MetaRNN

Benign

0.0065

T;T;T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-3.1

.;.;D;.

REVEL

Benign

0.17

Sift

Uncertain

0.026

.;.;D;.

Sift4G

Uncertain

0.0090

.;.;D;D

Vest4

0.062

ClinPred

0.032

GERP RS

1.2

Varity_R

0.089

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