rs755532803
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000784.4(CYP27A1):βc.666_678delβ(p.Phe222LeufsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. F222F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000784.4 frameshift
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.666_678del | p.Phe222LeufsTer13 | frameshift_variant | 4/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.666_678del | p.Phe222LeufsTer13 | frameshift_variant | 4/9 | 1 | NM_000784.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251402Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135884
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461888Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74374
ClinVar
Submissions by phenotype
Cholestanol storage disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change creates a premature translational stop signal (p.Phe222Leufs*13) 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 is present in population databases (rs755532803, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498394). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2018 | A variant that is likely pathogenic has been identified in the CYP27A1 gene. The c.666_678del13 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.666_678del13 variant causes a frameshift starting with codon Phenylalanine 222, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Phe222LeufsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.666_678del13 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 06, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at