rs7594289

Variant names:

• chr2-218787563-A-G
• rs7594289
• NM_000784.4:c.255+5126A>G

Variant summary

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

The NM_000784.4(CYP27A1):​c.255+5126A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 151,978 control chromosomes in the GnomAD database, including 10,354 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10354 hom., cov: 32)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.555
• Publications: 12 publications found

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A member 1) 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 mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 Gene-Disease associations (from GenCC):

• cerebrotendinous xanthomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.255+5126A>G		intron_variant	Intron 1 of 8	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.255+5126A>G		intron_variant	Intron 1 of 8	1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000445971.1	n.255+5126A>G		intron_variant	Intron 1 of 4	5		ENSP00000404945.1
CYP27A1	ENST00000466602.1	n.264+5126A>G		intron_variant	Intron 1 of 2	2
CYP27A1	ENST00000494263.5	n.689+5126A>G		intron_variant	Intron 1 of 6	2

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53958 AN: 151860 Hom.: 10350 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.0634

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.346

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.355 AC: 53974 AN: 151978 Hom.: 10354 Cov.: 32 AF XY: 0.354 AC XY: 26263 AN XY: 74268

African (AFR) AF: 0.246 AC: 10202 AN: 41454

American (AMR) AF: 0.365 AC: 5566 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3468

East Asian (EAS) AF: 0.0640 AC: 331 AN: 5174

South Asian (SAS) AF: 0.292 AC: 1403 AN: 4800

European-Finnish (FIN) AF: 0.484 AC: 5105 AN: 10550

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28879 AN: 67958

Other (OTH) AF: 0.347 AC: 733 AN: 2112

Alfa AF: 0.389 Hom.: 1472

Bravo AF: 0.343

Asia WGS AF: 0.196 AC: 685 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		-0.56
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: rs7594289; hg19: chr2-219652286;