NM_000784.4:c.255+3456C>T

Variant names:

• chr2-218785893-C-T
• rs933994
• NM_000784.4:c.255+3456C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000784.4(CYP27A1):​c.255+3456C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 152,044 control chromosomes in the GnomAD database, including 21,396 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 0.52 (21396 hom., cov: 32)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0190

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.255+3456C>T		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+3456C>T		intron_variant	Intron 1 of 8	1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000445971.1	n.255+3456C>T		intron_variant	Intron 1 of 4	5		ENSP00000404945.1
CYP27A1	ENST00000466602.1	n.264+3456C>T		intron_variant	Intron 1 of 2	2
CYP27A1	ENST00000494263.5	n.689+3456C>T		intron_variant	Intron 1 of 6	2

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78511 AN: 151926 Hom.: 21364 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.490

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

GnomAD4 genome AF: 0.517 AC: 78593 AN: 152044 Hom.: 21396 Cov.: 32 AF XY: 0.511 AC XY: 37975 AN XY: 74314

Gnomad4 AFR AF: 0.676

Gnomad4 AMR AF: 0.457

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.490

Alfa AF: 0.469 Hom.: 22149

Bravo AF: 0.520

Asia WGS AF: 0.287 AC: 999 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.4
DANN	Benign	0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs933994; hg19: chr2-219650616;