6-32041892-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001365276.2(TNXB):c.12512G>A(p.Arg4171His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 8 hom., cov: 12)

Exomes 𝑓: 0.00066 ( 13 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.230

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:

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP21A2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009919435).

BP6

Variant 6-32041892-C-T is Benign according to our data. Variant chr6-32041892-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224352.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00406 (397/97678) while in subpopulation AFR AF= 0.014 (357/25564). AF 95% confidence interval is 0.0128. There are 8 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 12. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.12512G>A	p.Arg4171His	missense_variant	Exon 43 of 44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9 link	c.*758C>T		downstream_gene_variant		ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.12512G>A	p.Arg4171His	missense_variant	Exon 43 of 44		NM_001365276.2	ENSP00000496448.1		P22105-3
CYP21A2	ENST00000644719.2 link	c.*758C>T		downstream_gene_variant			NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.00406

AC:

396

AN:

97580

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000109

Gnomad OTH

AF:

0.000790

GnomAD3 exomes

AF:

0.00124

AC:

140

AN:

113134

Hom.:

AF XY:

0.00105

AC XY:

AN XY:

60982

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000985

Gnomad OTH exome

AF:

0.000836

GnomAD4 exome

AF:

0.000660

AC:

394

AN:

596974

Hom.:

Cov.:

AF XY:

0.000515

AC XY:

162

AN XY:

314618

show subpopulations

Gnomad4 AFR exome

AF:

0.0145

Gnomad4 AMR exome

AF:

0.00223

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000160

Gnomad4 FIN exome

AF:

0.0000263

Gnomad4 NFE exome

AF:

0.0000416

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00406

AC:

397

AN:

97678

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

187

AN XY:

45362

show subpopulations

Gnomad4 AFR

AF:

0.0140

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000109

Gnomad4 OTH

AF:

0.000780

Alfa

AF:

0.00207

Hom.:

ExAC

AF:

0.000487

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vesicoureteral reflux 8

Uncertain:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

TNXB-related disorder

Uncertain:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TNXB c.12506G>A variant is predicted to result in the amino acid substitution p.Arg4169His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 1.5% of alleles in individuals of African descent in gnomAD. This variant is located within a highly paralogous region; population data frequency should be interpreted with caution. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Benign:1

Nov 20, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

T;.;T;.;T

Eigen

Benign

-0.035

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.033

LIST_S2

Uncertain

0.92

.;D;D;D;D

MetaRNN

Benign

0.0099

T;T;T;T;T

MetaSVM

Benign

-0.67

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.0

.;.;D;N;.

REVEL

Benign

0.29

Sift

Benign

0.25

.;.;T;T;.

Sift4G

Uncertain

0.0030

.;.;D;D;D

Vest4

0.17, 0.27

MVP

0.51

MPC

3.4

ClinPred

0.026

GERP RS

3.8

Varity_R

0.19

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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