rs204900

Positions:

chr6-32088803-A-C

Variant summary

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

The NM_001365276.2(TNXB):c.2761T>G(p.Ser921Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,575,098 control chromosomes in the GnomAD database, including 14,625 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2327 hom., cov: 32)

Exomes 𝑓: 0.11 ( 12298 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.46

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=0.003803134).

BP6

Variant 6-32088803-A-C is Benign according to our data. Variant chr6-32088803-A-C is described in ClinVar as [Benign]. Clinvar id is 261131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32088803-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 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.2761T>G	p.Ser921Ala	missense_variant	6/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.2761T>G	p.Ser921Ala	missense_variant	6/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.2761T>G	p.Ser921Ala	missense_variant	6/44		NM_001365276.2	ENSP00000496448		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.2761T>G	p.Ser921Ala	missense_variant	6/45			ENSP00000497649	P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.2761T>G	p.Ser921Ala	missense_variant	6/44	5		ENSP00000364393		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23139

AN:

152102

Hom.:

2314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.297

Gnomad FIN

AF:

0.0619

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.0963

Gnomad OTH

AF:

0.189

GnomAD3 exomes

AF:

0.136

AC:

26744

AN:

196842

Hom.:

2735

AF XY:

0.148

AC XY:

15583

AN XY:

105436

show subpopulations

Gnomad AFR exome

AF:

0.253

Gnomad AMR exome

AF:

0.0989

Gnomad ASJ exome

AF:

0.103

Gnomad EAS exome

AF:

0.102

Gnomad SAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.0647

Gnomad NFE exome

AF:

0.0955

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.110

AC:

157160

AN:

1422878

Hom.:

12298

Cov.:

AF XY:

0.118

AC XY:

82787

AN XY:

704100

show subpopulations

Gnomad4 AFR exome

AF:

0.267

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.341

Gnomad4 FIN exome

AF:

0.0678

Gnomad4 NFE exome

AF:

0.0895

Gnomad4 OTH exome

AF:

0.125

GnomAD4 genome

AF:

0.152

AC:

23177

AN:

152220

Hom.:

2327

Cov.:

AF XY:

0.155

AC XY:

11553

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.261

Gnomad4 AMR

AF:

0.149

Gnomad4 ASJ

AF:

0.111

Gnomad4 EAS

AF:

0.106

Gnomad4 SAS

AF:

0.297

Gnomad4 FIN

AF:

0.0619

Gnomad4 NFE

AF:

0.0963

Gnomad4 OTH

AF:

0.186

Alfa

AF:

0.112

Hom.:

2096

Bravo

AF:

0.159

TwinsUK

AF:

0.0847

AC:

314

ALSPAC

AF:

0.0955

AC:

368

ESP6500AA

AF:

0.231

AC:

946

ESP6500EA

AF:

0.0906

AC:

758

ExAC

AF:

0.121

AC:

14343

Asia WGS

AF:

0.249

AC:

866

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2018

This variant is associated with the following publications: (PMID: 16574953, 29379198) -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 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

0.19

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;.;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.61

.;T;T;T

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

.;.;N;.

REVEL

Benign

0.056

Sift

Benign

0.061

.;.;T;.

Sift4G

Uncertain

0.051

.;.;T;D

Vest4

0.12

ClinPred

0.022

GERP RS

5.4

Varity_R

0.14

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