rs149995364

Positions:

chr6-32084439-C-T

Variant summary

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

The NM_001365276.2(TNXB):c.3419G>A(p.Gly1140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,595,588 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 32)

Exomes 𝑓: 0.011 ( 272 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.95

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=0.0024562776).

BP6

Variant 6-32084439-C-T is Benign according to our data. Variant chr6-32084439-C-T is described in ClinVar as [Benign]. Clinvar id is 261135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32084439-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0128 (1949/152330) while in subpopulation AMR AF= 0.036 (551/15302). AF 95% confidence interval is 0.0335. There are 35 homozygotes in gnomad4. There are 879 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 35 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.3419G>A	p.Gly1140Asp	missense_variant	8/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.3419G>A	p.Gly1140Asp	missense_variant	8/44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.3419G>A	p.Gly1140Asp	missense_variant	8/44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.4160G>A	p.Gly1387Asp	missense_variant	9/45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 linkuse as main transcript	c.3419G>A	p.Gly1140Asp	missense_variant	8/44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1946

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00540

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0360

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0354

GnomAD3 exomes

AF:

0.0158

AC:

3840

AN:

242786

Hom.:

115

AF XY:

0.0143

AC XY:

1899

AN XY:

132862

show subpopulations

Gnomad AFR exome

AF:

0.00537

Gnomad AMR exome

AF:

0.0358

Gnomad ASJ exome

AF:

0.0991

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.00159

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0112

AC:

16188

AN:

1443258

Hom.:

272

Cov.:

AF XY:

0.0110

AC XY:

7871

AN XY:

715014

show subpopulations

Gnomad4 AFR exome

AF:

0.00595

Gnomad4 AMR exome

AF:

0.0362

Gnomad4 ASJ exome

AF:

0.0967

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00941

Gnomad4 OTH exome

AF:

0.0190

GnomAD4 genome

AF:

0.0128

AC:

1949

AN:

152330

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

879

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00541

Gnomad4 AMR

AF:

0.0360

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.0107

Gnomad4 OTH

AF:

0.0351

Alfa

AF:

0.0149

Hom.:

Bravo

AF:

0.0165

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00366

AC:

ESP6500EA

AF:

0.0128

AC:

ExAC

AF:

0.0133

AC:

1573

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0162

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

Apr 28, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 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

0.54

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;.;T;.

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.84

.;T;T;D

MetaRNN

Benign

0.0025

T;T;T;T

MetaSVM

Benign

-0.86

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.2

.;.;D;.

REVEL

Benign

0.26

Sift

Benign

0.091

.;.;T;.

Sift4G

Uncertain

0.0070

.;.;D;D

Vest4

0.20

ClinPred

0.039

GERP RS

4.2

Varity_R

0.31

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