rs200553205
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000784.4(CYP27A1):c.1017G>A(p.Thr339Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000715 in 1,607,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000784.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000930 AC: 23AN: 247182Hom.: 0 AF XY: 0.0000672 AC XY: 9AN XY: 133980
GnomAD4 exome AF: 0.0000660 AC: 96AN: 1455552Hom.: 0 Cov.: 32 AF XY: 0.0000719 AC XY: 52AN XY: 723124
GnomAD4 genome AF: 0.000125 AC: 19AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74470
ClinVar
Submissions by phenotype
Cholestanol storage disease Uncertain:4Benign:1
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This sequence change affects codon 339 of the CYP27A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CYP27A1 protein. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200553205, gnomAD 0.05%). 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: 284271). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
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Variant homozygously found in a 74 years old women without characteristic phenotype. RNA analysis revealed no effect on splicing. -
not specified Uncertain:1
Variant summary: CYP27A1 c.1017G>A (p.Thr339Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same 5' donor site. One submitter in ClinVar (SCV001468517.1) reports that the variant was found in the homozygous state in a 74 year old woman, where RNA analysis revealed no impact on splicing. However, this is yet to be confirmed by published functional studies. The variant allele was found at a frequency of 9.3e-05 in 247182 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CYP27A1 causing Cerebrotendinous Xanthomatosis (9.3e-05 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1017G>A in individuals affected with Cerebrotendinous Xanthomatosis and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at