rs397515355
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000784.4(CYP27A1):c.1263+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000069 ( 0 hom. )
Consequence
CYP27A1
NM_000784.4 splice_donor
NM_000784.4 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 8.13
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 22 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-218814459-G-A is Pathogenic according to our data. Variant chr2-218814459-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218814459-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CYP27A1 | NM_000784.4 | c.1263+1G>A | splice_donor_variant | ENST00000258415.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYP27A1 | ENST00000258415.9 | c.1263+1G>A | splice_donor_variant | 1 | NM_000784.4 | P1 | |||
| CYP27A1 | ENST00000494263.5 | n.1890G>A | non_coding_transcript_exon_variant | 6/7 | 2 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251476Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135908
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GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727242
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GnomAD4 genome 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74372
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cholestanol storage disease Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1999 | - - |
| Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 01, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 14, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 02, 2024 | Variant summary: CYP27A1 c.1263+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CYP27A1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Maddirevula_2020). The variant allele was found at a frequency of 2.8e-05 in 251476 control chromosomes (gnomAD). c.1263+1G>A has been reported in the literature in multiple individuals affected with Cerebrotendinous Xanthomatosis (e.g. Khan_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32552793, 26622071). ClinVar contains an entry for this variant (Variation ID: 4262). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 01, 2021 | NM_000784.3(CYP27A1):c.1263+1G>A is a canonical splice variant classified as pathogenic in the context of cerebrotendinous xanthomatosis. c.1263+1G>A has been observed in cases with relevant disease (PMID: 33313117, 22878431). Functional assessments of this variant are available in the literature (PMID: 8827518). c.1263+1G>A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000784.3(CYP27A1):c.1263+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change affects a donor splice site in intron 7 of the CYP27A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397515355, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with cerebrotendinous xanthomatosis (PMID: 8827518, 26622071, 27878435). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4262). Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 8827518). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2021 | Published functional studies demonstrate a damaging effect by skipping of exon 7 and a minimal amount of detectable mRNA product (Garuti et al., 1996); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26622071, 28894950, 25525159, 21104094, 22527785, 27878435, 22935719, 26874936, 23375591, 26153518, 10519880, 8827518, 33414089, 33830582, 16816916, 22878431, 28324197, 28937538, 31970228, 32552793, 32714376, 33269283, 33313117, 27706244, 26643207, 33967188, 34012265, 34689324, 20301583) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 23, 2015 | - - |
CYP27A1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 20, 2024 | The CYP27A1 c.1263+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in a homozygous state in several patient affected by cerebrotendinous xanthomatosis (CTX) (Garuti et al. 1996 PubMed ID: 8827518, Table S1, Maddirevula et al. 2020. PubMed ID: 32552793). Of note, substitutions of the same splice site, c.1263+1G>T and c.1263+5G>T, have been reported in CTX affected patients (Chang et al. 2022 PubMed ID: 36312475, Garuti et al. 1997. PubMed ID: 9392430). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in CYP27A1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at