6-32041892-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP21A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 224352.

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 the male GnomAd4 subpopulation. Median coverage is 12. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR,AD 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

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
CYP21A2	ENST00000644719.2 link	c.*758C>T		downstream_gene_variant			NM_000500.9	ENSP00000496625.1

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

GnomAD2 exomes

AF:

0.00124

AC:

140

AN:

113134

AF XY:

0.00105

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 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

African (AFR)

AF:

0.0145

AC:

251

AN:

17330

American (AMR)

AF:

0.00223

AC:

AN:

33172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18838

East Asian (EAS)

AF:

0.00

AC:

AN:

31970

South Asian (SAS)

AF:

0.0000160

AC:

AN:

62692

European-Finnish (FIN)

AF:

0.0000263

AC:

AN:

38044

Middle Eastern (MID)

AF:

0.000782

AC:

AN:

2556

European-Non Finnish (NFE)

AF:

0.0000416

AC:

AN:

360598

Other (OTH)

AF:

0.00157

AC:

AN:

31774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00406

AC:

397

AN:

97678

Hom.:

Cov.:

AF XY:

0.00412

AC XY:

187

AN XY:

45362

show subpopulations

African (AFR)

AF:

0.0140

AC:

357

AN:

25564

American (AMR)

AF:

0.00366

AC:

AN:

9286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2396

East Asian (EAS)

AF:

0.00

AC:

AN:

3832

South Asian (SAS)

AF:

0.00

AC:

AN:

2722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5836

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.000109

AC:

AN:

46024

Other (OTH)

AF:

0.000780

AC:

AN:

1282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

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

PhyloP100

0.23

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

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over