rs199953230

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001365276.2(TNXB):c.12530G>A(p.Ser4177Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.067 ( 23 hom., cov: 12)

Exomes 𝑓: 0.063 ( 733 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.728

Publications

12 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001997441).

BP6

Variant 6-32041874-C-T is Benign according to our data. Variant chr6-32041874-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190377.

BS2

High Homozygotes in GnomAdExome4 at 733 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.12530G>A	p.Ser4177Asn	missense_variant	Exon 43 of 44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9 link	c.*740C>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.12530G>A	p.Ser4177Asn	missense_variant	Exon 43 of 44		NM_001365276.2	ENSP00000496448.1
CYP21A2	ENST00000644719.2 link	c.*740C>T		downstream_gene_variant			NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes

AF:

0.0672

AC:

5778

AN:

86018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.0690

Gnomad AMR

AF:

0.0635

Gnomad ASJ

AF:

0.0770

Gnomad EAS

AF:

0.0198

Gnomad SAS

AF:

0.0718

Gnomad FIN

AF:

0.0294

Gnomad MID

AF:

0.0265

Gnomad NFE

AF:

0.0503

Gnomad OTH

AF:

0.0685

GnomAD2 exomes

AF:

0.0653

AC:

6962

AN:

106564

AF XY:

0.0728

show subpopulations

Gnomad AFR exome

AF:

0.0565

Gnomad AMR exome

AF:

0.0388

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.0144

Gnomad FIN exome

AF:

0.0760

Gnomad NFE exome

AF:

0.0587

Gnomad OTH exome

AF:

0.0680

GnomAD4 exome

AF:

0.0630

AC:

32038

AN:

508402

Hom.:

733

Cov.:

AF XY:

0.0664

AC XY:

17868

AN XY:

268916

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.130

AC:

1613

AN:

12388

American (AMR)

AF:

0.0596

AC:

1652

AN:

27716

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

1553

AN:

15390

East Asian (EAS)

AF:

0.00974

AC:

295

AN:

30294

South Asian (SAS)

AF:

0.102

AC:

5552

AN:

54404

European-Finnish (FIN)

AF:

0.0564

AC:

2149

AN:

38086

Middle Eastern (MID)

AF:

0.0714

AC:

147

AN:

2060

European-Non Finnish (NFE)

AF:

0.0578

AC:

17447

AN:

301746

Other (OTH)

AF:

0.0619

AC:

1630

AN:

26318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

2008

4016

6023

8031

10039

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

350

700

1050

1400

1750

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0672

AC:

5787

AN:

86100

Hom.:

Cov.:

AF XY:

0.0684

AC XY:

2787

AN XY:

40722

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.124

AC:

2459

AN:

19816

American (AMR)

AF:

0.0633

AC:

513

AN:

8106

Ashkenazi Jewish (ASJ)

AF:

0.0770

AC:

150

AN:

1948

East Asian (EAS)

AF:

0.0199

AC:

AN:

3668

South Asian (SAS)

AF:

0.0711

AC:

173

AN:

2434

European-Finnish (FIN)

AF:

0.0294

AC:

179

AN:

6086

Middle Eastern (MID)

AF:

0.0337

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0503

AC:

2127

AN:

42272

Other (OTH)

AF:

0.0673

AC:

AN:

1084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.328

Heterozygous variant carriers

363

726

1090

1453

1816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.106

Hom.:

ExAC

AF:

0.0764

AC:

2582

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency

Uncertain:1

Jan 01, 2015

Pediatric Services, National Institutes of Health, Clinical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:1

Mar 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4_strong -

not specified

Benign:1

Jun 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0021

.;.;.;.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.018

.;T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.73

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

1.8

.;.;N;N;.

REVEL

Benign

0.22

Sift

Benign

0.55

.;.;T;T;.

Sift4G

Benign

1.0

.;.;T;T;T

Vest4

0.060, 0.092

MPC

1.5

ClinPred

0.0059

GERP RS

4.7

Varity_R

0.061

gMVP

0.076

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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