rs1178393503
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000784.4(CYP27A1):c.1180_1181del(p.Leu394AlafsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000372 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CYP27A1
NM_000784.4 frameshift
NM_000784.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.06
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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-218814180-ACT-A is Pathogenic according to our data. Variant chr2-218814180-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558186.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.1180_1181del | p.Leu394AlafsTer18 | frameshift_variant | 6/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.1180_1181del | p.Leu394AlafsTer18 | frameshift_variant | 6/9 | 1 | NM_000784.4 | P1 | |
CYP27A1 | ENST00000494263.5 | n.1614_1615del | non_coding_transcript_exon_variant | 6/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151976Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251338Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135852
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461888Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727242
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151976Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74236
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cholestanol storage disease Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 26, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 02, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 558186). This variant is also known as Ex6Δ2bp. This premature translational stop signal has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 11181744). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Leu394Alafs*18) 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 03, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 30, 2020 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at