dbSNP rs886041342: CYP27A1:p.Leu4ArgfsTer3 (chr2-218782184-TGGCTGCGCTG-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000784.4(CYP27A1):c.11_20delTGGGCTGCGC(p.Leu4ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,384,210 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.60

Publications

0 publications found

Variant links:

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

CYP27A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 175 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4 link	c.11_20delTGGGCTGCGC	p.Leu4ArgfsTer3	frameshift_variant	Exon 1 of 9	ENST00000258415.9	NP_000775.1	Q02318

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP27A1	ENST00000258415.9 link	c.11_20delTGGGCTGCGC	p.Leu4ArgfsTer3	frameshift_variant	Exon 1 of 9	1	NM_000784.4	ENSP00000258415.4	Q02318
CYP27A1	ENST00000445971.1 link	n.11_20delTGGGCTGCGC		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000404945.1	F8WD90
CYP27A1	ENST00000466602.1 link	n.20_29delTGGGCTGCGC		non_coding_transcript_exon_variant	Exon 1 of 3	2
CYP27A1	ENST00000494263.5 link	n.445_454delTGGGCTGCGC		non_coding_transcript_exon_variant	Exon 1 of 7	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000289

AC:

AN:

1384210

Hom.:

AF XY:

0.00000586

AC XY:

AN XY:

683160

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31354

American (AMR)

AF:

0.00

AC:

AN:

35626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25108

East Asian (EAS)

AF:

0.00

AC:

AN:

35674

South Asian (SAS)

AF:

0.0000506

AC:

AN:

79114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078062

Other (OTH)

AF:

0.00

AC:

AN:

57660

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=25/175

disease causing

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over