6-32052940-G-T

Position:

chr6-32052940-G-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.8845C>A(p.Pro2949Thr) 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 1,612,740 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 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. P2949S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 32)

Exomes 𝑓: 0.011 ( 278 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.12

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=0.0022907555).

BP6

Variant 6-32052940-G-T is Benign according to our data. Variant chr6-32052940-G-T is described in ClinVar as [Benign]. Clinvar id is 261172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32052940-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0129 (1967/152278) while in subpopulation AMR AF= 0.0361 (552/15298). AF 95% confidence interval is 0.0336. There are 35 homozygotes in gnomad4. There are 886 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	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.8845C>A	p.Pro2949Thr	missense_variant	26/44	ENST00000644971.2
TNXB	NM_019105.8 linkuse as main transcript	c.8839C>A	p.Pro2947Thr	missense_variant	26/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.8845C>A	p.Pro2949Thr	missense_variant	26/44		NM_001365276.2		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.9586C>A	p.Pro3196Thr	missense_variant	27/45			P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.8845C>A	p.Pro2949Thr	missense_variant	26/44	5			P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1964

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0361

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0359

GnomAD3 exomes

AF:

0.0160

AC:

3879

AN:

242894

Hom.:

117

AF XY:

0.0144

AC XY:

1914

AN XY:

133094

show subpopulations

Gnomad AFR exome

AF:

0.00611

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.0000560

Gnomad SAS exome

AF:

0.00184

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0112

AC:

16417

AN:

1460462

Hom.:

278

Cov.:

AF XY:

0.0110

AC XY:

8021

AN XY:

726534

show subpopulations

Gnomad4 AFR exome

AF:

0.00675

Gnomad4 AMR exome

AF:

0.0363

Gnomad4 ASJ exome

AF:

0.0970

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.00147

Gnomad4 NFE exome

AF:

0.00943

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0129

AC:

1967

AN:

152278

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

886

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00580

Gnomad4 AMR

AF:

0.0361

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:

0.0355

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0166

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00434

AC:

ESP6500EA

AF:

0.0126

AC:

ExAC

AF:

0.0135

AC:

1587

EpiCase

AF:

0.0149

EpiControl

AF:

0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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

Benign

0.060

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.1

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

.;.;.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.087

.;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.2

.;.;D;.

REVEL

Benign

0.085

Sift

Uncertain

0.018

.;.;D;.

Sift4G

Uncertain

0.0070

.;.;D;D

Vest4

0.025

ClinPred

0.034

GERP RS

1.5

Varity_R

0.069

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