rs61746206

Positions:

chr6-32097336-C-T

Variant summary

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

The NM_001365276.2(TNXB):c.517G>A(p.Ala173Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,613,458 control chromosomes in the GnomAD database, including 1,362 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 62 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1300 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.08

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=0.0015425086).

BP6

Variant 6-32097336-C-T is Benign according to our data. Variant chr6-32097336-C-T is described in ClinVar as [Benign]. Clinvar id is 261140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32097336-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 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.517G>A	p.Ala173Thr	missense_variant	3/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.517G>A	p.Ala173Thr	missense_variant	3/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.517G>A	p.Ala173Thr	missense_variant	3/44		NM_001365276.2	ENSP00000496448		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

3024

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00975

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.0550

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0347

AC:

8613

AN:

247940

Hom.:

423

AF XY:

0.0398

AC XY:

5365

AN XY:

134714

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.00728

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.0526

Gnomad SAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0205

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0259

AC:

37797

AN:

1461162

Hom.:

1300

Cov.:

AF XY:

0.0289

AC XY:

21019

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.00935

Gnomad4 AMR exome

AF:

0.00734

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.0746

Gnomad4 SAS exome

AF:

0.127

Gnomad4 FIN exome

AF:

0.0209

Gnomad4 NFE exome

AF:

0.0180

Gnomad4 OTH exome

AF:

0.0276

GnomAD4 genome

AF:

0.0198

AC:

3023

AN:

152296

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1662

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0106

Gnomad4 AMR

AF:

0.00974

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.0550

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.0180

Gnomad4 NFE

AF:

0.0194

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0193

Hom.:

Bravo

AF:

0.0161

TwinsUK

AF:

0.0170

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.0119

AC:

ESP6500EA

AF:

0.0171

AC:

144

ExAC

AF:

0.0364

AC:

4403

Asia WGS

AF:

0.136

AC:

470

AN:

3478

EpiCase

AF:

0.0196

EpiControl

AF:

0.0189

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 09, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 24036952) -

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

0.063

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.51

DANN

Benign

0.70

DEOGEN2

Benign

0.030

T;.;T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.67

.;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.68

.;.;N;.;N

REVEL

Benign

0.14

Sift

Benign

0.79

.;.;T;.;T

Sift4G

Benign

0.76

.;.;T;T;T

Vest4

0.021, 0.042

ClinPred

0.0026

GERP RS

-8.8

Varity_R

0.029

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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