rs587778785
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_000784.4(CYP27A1):c.1264-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 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_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP27A1 | NM_000784.4 | c.1264-1G>A | splice_acceptor_variant | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.1264-1G>A | splice_acceptor_variant | 1 | NM_000784.4 | P1 | |||
CYP27A1 | ENST00000494263.5 | n.1975G>A | non_coding_transcript_exon_variant | 6/7 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251078Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135832
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cholestanol storage disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2023 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Aug 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant is associated with altered splicing, resulting in an in-frame deletion in exon 8 or inclusion of intron 7 (PMID: 9392430). ClinVar contains an entry for this variant (Variation ID: 65844). This variant is also known as In 7 G-1>A. Disruption of this splice site has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 9392430). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs587778785, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 7 of the CYP27A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYP27A1 are known to be pathogenic (PMID: 9392430, 10775536, 26937392). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at