NM_000784.4:c.255+5213G>A

Variant names:

• chr2-218787650-G-A
• rs7568196
• NM_000784.4:c.255+5213G>A

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+5213G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 151,902 control chromosomes in the GnomAD database, including 9,281 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 0.34 (9281 hom., cov: 31)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.521
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.255+5213G>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+5213G>A		intron_variant	Intron 1 of 8	1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000445971.1	n.255+5213G>A		intron_variant	Intron 1 of 4	5		ENSP00000404945.1
CYP27A1	ENST00000466602.1	n.264+5213G>A		intron_variant	Intron 1 of 2	2
CYP27A1	ENST00000494263.5	n.689+5213G>A		intron_variant	Intron 1 of 6	2

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51214 AN: 151784 Hom.: 9277 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.369

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.0615

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.335

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

GnomAD4 genome AF: 0.337 AC: 51228 AN: 151902 Hom.: 9281 Cov.: 31 AF XY: 0.336 AC XY: 24914 AN XY: 74230

African (AFR) AF: 0.239 AC: 9896 AN: 41420

American (AMR) AF: 0.350 AC: 5348 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3468

East Asian (EAS) AF: 0.0621 AC: 321 AN: 5172

South Asian (SAS) AF: 0.283 AC: 1366 AN: 4824

European-Finnish (FIN) AF: 0.439 AC: 4621 AN: 10526

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27262 AN: 67916

Other (OTH) AF: 0.337 AC: 711 AN: 2112

Alfa AF: 0.344 Hom.: 2297

Bravo AF: 0.328

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.7
DANN	Benign	0.64
PhyloP100		0.52
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: rs7568196; hg19: chr2-219652373;