6-32049396-G-C

Position:

chr6-32049396-G-C

Variant summary

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

The NM_001365276.2(TNXB):c.9631C>G(p.Arg3211Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 1,612,554 control chromosomes in the GnomAD database, including 1,923 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. R3211H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.038 ( 221 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1702 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.41

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=0.0019940138).

BP6

Variant 6-32049396-G-C is Benign according to our data. Variant chr6-32049396-G-C is described in ClinVar as [Benign]. Clinvar id is 261179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32049396-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0376 (5725/152236) while in subpopulation NFE AF= 0.0463 (3150/68008). AF 95% confidence interval is 0.045. There are 221 homozygotes in gnomad4. There are 3072 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 221 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.9631C>G	p.Arg3211Gly	missense_variant	28/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.9625C>G	p.Arg3209Gly	missense_variant	28/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.9631C>G	p.Arg3211Gly	missense_variant	28/44		NM_001365276.2		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.10372C>G	p.Arg3458Gly	missense_variant	29/45			P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.9631C>G	p.Arg3211Gly	missense_variant	28/44	5			P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

5724

AN:

152118

Hom.:

221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00729

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.0229

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.0189

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0463

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0390

AC:

9626

AN:

246914

Hom.:

359

AF XY:

0.0392

AC XY:

5264

AN XY:

134342

show subpopulations

Gnomad AFR exome

AF:

0.00790

Gnomad AMR exome

AF:

0.0152

Gnomad ASJ exome

AF:

0.00530

Gnomad EAS exome

AF:

0.00178

Gnomad SAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.145

Gnomad NFE exome

AF:

0.0458

Gnomad OTH exome

AF:

0.0390

GnomAD4 exome

AF:

0.0413

AC:

60306

AN:

1460318

Hom.:

1702

Cov.:

AF XY:

0.0406

AC XY:

29515

AN XY:

726464

show subpopulations

Gnomad4 AFR exome

AF:

0.00586

Gnomad4 AMR exome

AF:

0.0162

Gnomad4 ASJ exome

AF:

0.00520

Gnomad4 EAS exome

AF:

0.00136

Gnomad4 SAS exome

AF:

0.0154

Gnomad4 FIN exome

AF:

0.140

Gnomad4 NFE exome

AF:

0.0435

Gnomad4 OTH exome

AF:

0.0321

GnomAD4 genome

AF:

0.0376

AC:

5725

AN:

152236

Hom.:

221

Cov.:

AF XY:

0.0413

AC XY:

3072

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00727

Gnomad4 AMR

AF:

0.0229

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00406

Gnomad4 SAS

AF:

0.0195

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.0463

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0310

Hom.:

Bravo

AF:

0.0263

TwinsUK

AF:

0.0426

AC:

158

ALSPAC

AF:

0.0464

AC:

179

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0467

AC:

238

ExAC

AF:

0.0389

AC:

4697

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0440

EpiControl

AF:

0.0415

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 05, 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

0.13

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

T;.;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.90

.;D;D;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.9

.;.;D;.

REVEL

Benign

0.23

Sift

Benign

0.39

.;.;T;.

Sift4G

Uncertain

0.015

.;.;D;D

Vest4

0.21

ClinPred

0.041

GERP RS

4.4

Varity_R

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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