rs28361051

Positions:

chr6-32056597-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001365276.2(TNXB):c.8132T>C(p.Ile2711Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,612,982 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 15 hom., cov: 32)

Exomes 𝑓: 0.010 ( 115 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.499

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036107898).

BP6

Variant 6-32056597-A-G is Benign according to our data. Variant chr6-32056597-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32056597-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.8132T>C	p.Ile2711Thr	missense_variant	23/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.8132T>C	p.Ile2711Thr	missense_variant	23/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.8132T>C	p.Ile2711Thr	missense_variant	23/44		NM_001365276.2		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.8873T>C	p.Ile2958Thr	missense_variant	24/45			P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.8132T>C	p.Ile2711Thr	missense_variant	23/44	5			P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00990

AC:

1507

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.00523

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.0292

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0124

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00993

AC:

2436

AN:

245218

Hom.:

AF XY:

0.0104

AC XY:

1393

AN XY:

133814

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00354

Gnomad ASJ exome

AF:

0.0359

Gnomad EAS exome

AF:

0.000391

Gnomad SAS exome

AF:

0.00533

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0103

AC:

15105

AN:

1460684

Hom.:

115

Cov.:

AF XY:

0.0105

AC XY:

7595

AN XY:

726618

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.00391

Gnomad4 ASJ exome

AF:

0.0342

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00502

Gnomad4 FIN exome

AF:

0.0255

Gnomad4 NFE exome

AF:

0.0105

Gnomad4 OTH exome

AF:

0.00861

GnomAD4 genome

AF:

0.00990

AC:

1507

AN:

152298

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

814

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00523

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.0292

Gnomad4 NFE

AF:

0.0124

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.0143

Hom.:

Bravo

AF:

0.00739

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00120

AC:

ESP6500EA

AF:

0.00985

AC:

ExAC

AF:

0.00897

AC:

1081

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0124

EpiControl

AF:

0.00937

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TNXB: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	- -

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

May 27, 2022

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 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

0.081

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.97

DANN

Benign

0.80

DEOGEN2

Benign

0.066

T;.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.17

.;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.5

.;.;N;.

REVEL

Benign

0.027

Sift

Benign

0.29

.;.;T;.

Sift4G

Benign

0.18

.;.;T;T

Vest4

0.031

MVP

0.13

ClinPred

0.0041

GERP RS

2.0

Varity_R

0.086

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