rs370868184
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_000784.4(CYP27A1):c.1343G>A(p.Arg448His) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,614,068 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. R448C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000784.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP27A1 | NM_000784.4 | c.1343G>A | p.Arg448His | missense_variant | 8/9 | ENST00000258415.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27A1 | ENST00000258415.9 | c.1343G>A | p.Arg448His | missense_variant | 8/9 | 1 | NM_000784.4 | P1 | |
CYP27A1 | ENST00000494263.5 | n.2055G>A | non_coding_transcript_exon_variant | 6/7 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250020Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135736
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727240
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74338
ClinVar
Submissions by phenotype
Cholestanol storage disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 448 of the CYP27A1 protein (p.Arg448His). This variant is present in population databases (rs370868184, gnomAD 0.04%). 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: 198750). 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. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 31, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at