rs200523717

Variant names:

• chr6-32041884-C-T
• rs200523717
• NM_001365276.2:c.12520G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365276.2(TNXB):​c.12520G>A​(p.Asp4174Asn) variant causes a missense change. 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 0.093 (27 hom., cov: 11)
  • Exomes 𝑓: 0.094 (730 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.03
• Publications: 11 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008031756).
• BP6: Variant 6-32041884-C-T is Benign according to our data. Variant chr6-32041884-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190376.
• BS2: High Homozygotes in GnomAdExome4 at 730 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12520G>A	p.Asp4174Asn	missense_variant	Exon 43 of 44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9	c.*750C>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	c.12520G>A	p.Asp4174Asn	missense_variant	Exon 43 of 44		NM_001365276.2	ENSP00000496448.1
CYP21A2	ENST00000644719.2	c.*750C>T		downstream_gene_variant			NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.0933 AC: 7579 AN: 81200 Hom.: 27 Cov.: 11

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.0543

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0987

Gnomad EAS AF: 0.0562

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0481

Gnomad MID AF: 0.0374

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.0930

GnomAD2 exomes AF: 0.0966 AC: 9659 AN: 99992 AF XY: 0.111

Gnomad AFR exome AF: 0.0684

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0767

Gnomad OTH exome AF: 0.0912

GnomAD4 exome AF: 0.0936 AC: 46105 AN: 492734 Hom.: 730 Cov.: 6 AF XY: 0.0996 AC XY: 25901 AN XY: 259990

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

African (AFR) AF: 0.149 AC: 1814 AN: 12170

American (AMR) AF: 0.0685 AC: 1880 AN: 27438

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 1741 AN: 15072

East Asian (EAS) AF: 0.0517 AC: 1490 AN: 28840

South Asian (SAS) AF: 0.196 AC: 9823 AN: 50146

European-Finnish (FIN) AF: 0.0767 AC: 2757 AN: 35962

Middle Eastern (MID) AF: 0.0855 AC: 174 AN: 2034

European-Non Finnish (NFE) AF: 0.0816 AC: 24102 AN: 295498

Other (OTH) AF: 0.0909 AC: 2324 AN: 25574

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0934 AC: 7588 AN: 81276 Hom.: 27 Cov.: 11 AF XY: 0.0970 AC XY: 3698 AN XY: 38130

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

African (AFR) AF: 0.151 AC: 2864 AN: 18948

American (AMR) AF: 0.0817 AC: 616 AN: 7544

Ashkenazi Jewish (ASJ) AF: 0.0987 AC: 180 AN: 1824

East Asian (EAS) AF: 0.0567 AC: 194 AN: 3424

South Asian (SAS) AF: 0.173 AC: 366 AN: 2110

European-Finnish (FIN) AF: 0.0481 AC: 267 AN: 5554

Middle Eastern (MID) AF: 0.0455 AC: 9 AN: 198

European-Non Finnish (NFE) AF: 0.0740 AC: 2975 AN: 40216

Other (OTH) AF: 0.0915 AC: 93 AN: 1016

⚠️ 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.

Alfa AF: 0.123 Hom.: 76

ExAC AF: 0.126 AC: 3546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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

- -

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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;.;.;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.86	.;D;D;D;D
MetaRNN	Benign	0.0080	T;T;T;T;T
MetaSVM	Uncertain	0.62	D
PhyloP100		5.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	.;.;D;D;.
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	.;.;D;D;.
Sift4G	Uncertain	0.013	.;.;D;T;D
Vest4		0.20, 0.58
MPC		2.9
ClinPred		0.017	T
GERP RS		4.7
Varity_R		0.73
gMVP		0.64
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200523717; hg19: chr6-32009661; COSMIC: COSV64475182; COSMIC: COSV64475182;