rs4674338

Variant names:

• chr2-218782764-G-A
• rs4674338
• NM_000784.4:c.255+327G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000784.4(CYP27A1):​c.255+327G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 151,902 control chromosomes in the GnomAD database, including 10,579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.36 (10579 hom., cov: 31)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.34
• Publications: 27 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-218782764-G-A is Benign according to our data. Variant chr2-218782764-G-A is described in ClinVar as Benign. ClinVar VariationId is 1275608.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.255+327G>A		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+327G>A		intron_variant	Intron 1 of 8	1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000445971.1	n.255+327G>A		intron_variant	Intron 1 of 4	5		ENSP00000404945.1
CYP27A1	ENST00000466602.1	n.264+327G>A		intron_variant	Intron 1 of 2	2
CYP27A1	ENST00000494263.5	n.689+327G>A		intron_variant	Intron 1 of 6	2

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54858 AN: 151784 Hom.: 10571 Cov.: 31

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.349

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

GnomAD4 genome AF: 0.361 AC: 54892 AN: 151902 Hom.: 10579 Cov.: 31 AF XY: 0.360 AC XY: 26715 AN XY: 74228

African (AFR) AF: 0.270 AC: 11199 AN: 41426

American (AMR) AF: 0.366 AC: 5591 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3472

East Asian (EAS) AF: 0.0631 AC: 326 AN: 5164

South Asian (SAS) AF: 0.291 AC: 1402 AN: 4818

European-Finnish (FIN) AF: 0.485 AC: 5099 AN: 10516

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28820 AN: 67930

Other (OTH) AF: 0.350 AC: 739 AN: 2112

Alfa AF: 0.396 Hom.: 23364

Bravo AF: 0.350

Asia WGS AF: 0.200 AC: 699 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.55
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4674338; hg19: chr2-219647487;