rs4674345

Variant names:

• chr2-218806875-A-G
• rs4674345
• NM_000784.4:c.256-2702A>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.256-2702A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,518 control chromosomes in the GnomAD database, including 16,429 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 0.46 (16429 hom., cov: 30)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.229
• Publications: 23 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.499 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.256-2702A>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.256-2702A>G		intron_variant	Intron 1 of 8	1	NM_000784.4	ENSP00000258415.4

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69468 AN: 151402 Hom.: 16427 Cov.: 30

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.459 AC: 69495 AN: 151518 Hom.: 16429 Cov.: 30 AF XY: 0.456 AC XY: 33725 AN XY: 73982

African (AFR) AF: 0.422 AC: 17389 AN: 41252

American (AMR) AF: 0.431 AC: 6566 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1513 AN: 3464

East Asian (EAS) AF: 0.166 AC: 859 AN: 5178

South Asian (SAS) AF: 0.363 AC: 1745 AN: 4810

European-Finnish (FIN) AF: 0.558 AC: 5782 AN: 10368

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.504 AC: 34194 AN: 67912

Other (OTH) AF: 0.456 AC: 956 AN: 2098

Alfa AF: 0.485 Hom.: 32788

Bravo AF: 0.450

Asia WGS AF: 0.286 AC: 996 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.3
DANN	Benign	0.78
PhyloP100		0.23
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: rs4674345; hg19: chr2-219671598;