rs397515355
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
Consequence
NM_000784.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
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 ? AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251476Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135908
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727242
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74372
ClinVar
Submissions by phenotype
Cholestanol storage disease Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 14, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
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, no assertion criteria provided | curation | GeneReviews | Aug 01, 2013 | - - |
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 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at