rs587778802
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000784.4(CYP27A1):c.5dup(p.Ala3CysfsTer178) 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 1,384,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Consequence
CYP27A1
NM_000784.4 frameshift
NM_000784.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.512
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 147 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-218782186-G-GC is Pathogenic according to our data. Variant chr2-218782186-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 65882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP27A1 | NM_000784.4 | c.5dup | p.Ala3CysfsTer178 | frameshift_variant | 1/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.5dup | p.Ala3CysfsTer178 | frameshift_variant | 1/9 | 1 | NM_000784.4 | P1 | |
CYP27A1 | ENST00000466602.1 | n.14dup | non_coding_transcript_exon_variant | 1/3 | 2 | ||||
CYP27A1 | ENST00000494263.5 | n.439dup | non_coding_transcript_exon_variant | 1/7 | 2 | ||||
CYP27A1 | ENST00000445971.1 | c.5dup | p.Ala3CysfsTer96 | frameshift_variant, NMD_transcript_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000289 AC: 4AN: 1384028Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2AN XY: 683002
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cholestanol storage disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2020 | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Ala3Cysfs*178) in the CYP27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). This variant has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 7860076). It is also known as c.6insC. ClinVar contains an entry for this variant (Variation ID: 65882). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 01, 2024 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 7860076) - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at