rs72551320

Positions:

• chr2-218814064-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000784.4(CYP27A1):​c.1061A>G​(p.Asp354Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP27A1 NM_000784.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.04

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 2-218814064-A-G is Pathogenic according to our data. Variant chr2-218814064-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 65827.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-218814064-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.1061A>G	p.Asp354Gly	missense_variant	6/9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.1061A>G	p.Asp354Gly	missense_variant	6/9	1	NM_000784.4	ENSP00000258415	P1
CYP27A1	ENST00000466602.1	n.1183A>G		non_coding_transcript_exon_variant	3/3	2
CYP27A1	ENST00000494263.5	n.1495A>G		non_coding_transcript_exon_variant	6/7	2
CYP27A1	ENST00000445971.1	c.*522A>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	5		ENSP00000404945

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cholestanol storage disease Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Aug 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.35
Sift	Benign	0.055	T
Sift4G	Benign	0.15	T
Polyphen		0.15	B
Vest4		0.75
MutPred		0.88		Loss of stability (P = 0.032);
MVP		0.79
MPC		0.30
ClinPred		0.35	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs72551320; hg19: chr2-219678787;