rs1245201394
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000784.4(CYP27A1):c.1175A>C(p.Glu392Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E392K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000784.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP27A1 | NM_000784.4 | c.1175A>C | p.Glu392Ala | missense_variant | 6/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.1175A>C | p.Glu392Ala | missense_variant | 6/9 | 1 | NM_000784.4 | P1 | |
CYP27A1 | ENST00000494263.5 | n.1609A>C | non_coding_transcript_exon_variant | 6/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251350Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135860
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727240
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74372
ClinVar
Submissions by phenotype
Cholestanol storage disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 07, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 06, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 392 of the CYP27A1 protein (p.Glu392Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with cerebrotendinous xanthomatosis (PMID: 19373932). This variant is also known as E359A. ClinVar contains an entry for this variant (Variation ID: 500465). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP27A1 protein function. This variant disrupts the p.Glu392 amino acid residue in CYP27A1. Other variant(s) that disrupt this residue have been observed in individuals with CYP27A1-related conditions (PMID: 27455001), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 23, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at