rs6447

Variant names:

• chr6-32041147-G-A
• rs6447
• NM_000500.9:c.*13G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32041147-G-A
• chr6-32041147-G-C
• chr6-32041147-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000500.9(CYP21A2):​c.*13G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,587,566 control chromosomes in the GnomAD database, including 685 homozygotes. 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 0.016 (58 hom., cov: 33)
  • Exomes 𝑓: 0.017 (627 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:3
• Conservation: PhyloP100: -0.598
• Publications: 11 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.*13G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4
TNXB	NM_001365276.2	c.*202C>T		downstream_gene_variant		ENST00000644971.2	NP_001352205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*13G>A		3_prime_UTR_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1
TNXB	ENST00000644971.2	c.*202C>T		downstream_gene_variant			NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2380 AN: 151294 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00393

Gnomad AMI AF: 0.0100

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00659

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.0253 AC: 5997 AN: 236776 AF XY: 0.0233

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.0593

Gnomad ASJ exome AF: 0.00493

Gnomad EAS exome AF: 0.0755

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0173 AC: 24837 AN: 1436150 Hom.: 627 Cov.: 33 AF XY: 0.0171 AC XY: 12261 AN XY: 714970

African (AFR) AF: 0.00267 AC: 89 AN: 33352

American (AMR) AF: 0.0513 AC: 2263 AN: 44140

Ashkenazi Jewish (ASJ) AF: 0.00581 AC: 148 AN: 25460

East Asian (EAS) AF: 0.0625 AC: 2455 AN: 39302

South Asian (SAS) AF: 0.0164 AC: 1401 AN: 85656

European-Finnish (FIN) AF: 0.0193 AC: 910 AN: 47132

Middle Eastern (MID) AF: 0.00770 AC: 33 AN: 4286

European-Non Finnish (NFE) AF: 0.0152 AC: 16657 AN: 1097246

Other (OTH) AF: 0.0148 AC: 881 AN: 59576

GnomAD4 genome AF: 0.0157 AC: 2378 AN: 151416 Hom.: 58 Cov.: 33 AF XY: 0.0160 AC XY: 1186 AN XY: 73984

African (AFR) AF: 0.00392 AC: 163 AN: 41572

American (AMR) AF: 0.0282 AC: 427 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.00659 AC: 22 AN: 3340

East Asian (EAS) AF: 0.0688 AC: 352 AN: 5118

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4804

European-Finnish (FIN) AF: 0.0198 AC: 207 AN: 10432

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1081 AN: 67694

Other (OTH) AF: 0.0171 AC: 36 AN: 2100

Alfa AF: 0.0139 Hom.: 17

Bravo AF: 0.0173

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:2 Uncertain:2 Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP4 -

not provided Uncertain:1 Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 18, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. This variant is located in a genomic region of low or unreliable sequencing quality, and therefore estimations of its population frequency are uninformative in assessment of variant pathogenicity. This variant has been seen in trans with other recessive pathogenic CYP21A2 variants in multiple individuals with classic and also nonclassic forms of CAH. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Results from PMID: 21521936 show a reduction in mRNA levels due to this variant, however, neither protein levels nor protein activity were assayed. This variant is also referred to by nucleotide 4397 in some published literature, and has been previously reported by Athena Diagnostics at nucleotide 1501. -

CYP21A2-related disorder Uncertain:1

Jun 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CYP21A2 c.*13G>A variant is located in the 3' untranslated region. This particular variant has been previously reported to be associated with a mild form of congenital adrenal hyperplasia (CAH) (Menabò et al. 2012. PubMed ID: 21521936). Its minor allele frequency is up to ~7.5% in East Asian individuals. However, this minor allele frequency is based on the current next-generation sequencing technology and may not be an accurate estimate because this variant is located within a highly homologous sequence region (Mandelker et al. 2016. PubMed ID: 27228465). Due to limited functional and genetic evidence, the clinical significance of the c.*13G>A variant is currently uncertain. -

not specified Benign:1

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.64
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6447; hg19: chr6-32008924; COSMIC: COSV64478062; COSMIC: COSV64478062;