rs9267795

Positions:

Variant summary

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

The NM_001365276.2(TNXB):c.9641G>T(p.Gly3214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,612,534 control chromosomes in the GnomAD database, including 402 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3214R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.025 ( 86 hom., cov: 32)

Exomes 𝑓: 0.016 ( 316 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.25

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=0.0028644204).

BP6

Variant 6-32049386-C-A is Benign according to our data. Variant chr6-32049386-C-A is described in ClinVar as [Benign]. Clinvar id is 261180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0245 (3733/152254) while in subpopulation AFR AF= 0.0444 (1846/41534). AF 95% confidence interval is 0.0428. There are 86 homozygotes in gnomad4. There are 1794 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 86 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.9641G>T	p.Gly3214Val	missense_variant	28/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.9635G>T	p.Gly3212Val	missense_variant	28/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.9641G>T	p.Gly3214Val	missense_variant	28/44		NM_001365276.2		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.10382G>T	p.Gly3461Val	missense_variant	29/45			P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.9641G>T	p.Gly3214Val	missense_variant	28/44	5			P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3730

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0446

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0298

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.0433

Gnomad SAS

AF:

0.0223

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.0349

GnomAD3 exomes

AF:

0.0202

AC:

4993

AN:

247122

Hom.:

102

AF XY:

0.0201

AC XY:

2707

AN XY:

134426

show subpopulations

Gnomad AFR exome

AF:

0.0443

Gnomad AMR exome

AF:

0.0216

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.0597

Gnomad SAS exome

AF:

0.0263

Gnomad FIN exome

AF:

0.00283

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0188

GnomAD4 exome

AF:

0.0158

AC:

23060

AN:

1460280

Hom.:

316

Cov.:

AF XY:

0.0160

AC XY:

11599

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.0438

Gnomad4 AMR exome

AF:

0.0223

Gnomad4 ASJ exome

AF:

0.0118

Gnomad4 EAS exome

AF:

0.0244

Gnomad4 SAS exome

AF:

0.0276

Gnomad4 FIN exome

AF:

0.00347

Gnomad4 NFE exome

AF:

0.0141

Gnomad4 OTH exome

AF:

0.0167

GnomAD4 genome

AF:

0.0245

AC:

3733

AN:

152254

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

1794

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0444

Gnomad4 AMR

AF:

0.0297

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.0436

Gnomad4 SAS

AF:

0.0226

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.0271

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.0408

AC:

105

ESP6500EA

AF:

0.0169

AC:

ExAC

AF:

0.0202

AC:

2440

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0152

EpiControl

AF:

0.0160

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 18, 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

Uncertain

0.35

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.12

.;.;.;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.62

.;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T

MetaSVM

Benign

-0.86

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.0

.;.;D;.

REVEL

Benign

0.18

Sift

Uncertain

0.023

.;.;D;.

Sift4G

Pathogenic

0.0010

.;.;D;D

Vest4

0.19

ClinPred

0.040

GERP RS

3.5

Varity_R

0.45

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