rs387906260
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000785.4(CYP27B1):c.262del(p.Val88TrpfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,546,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V88V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000785.4 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 |
---|---|---|---|---|---|---|---|
CYP27B1 | NM_000785.4 | c.262del | p.Val88TrpfsTer71 | frameshift_variant | 2/9 | ENST00000228606.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP27B1 | ENST00000228606.9 | c.262del | p.Val88TrpfsTer71 | frameshift_variant | 2/9 | 1 | NM_000785.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000350 AC: 5AN: 142666Hom.: 0 AF XY: 0.0000388 AC XY: 3AN XY: 77314
GnomAD4 exome AF: 0.0000301 AC: 42AN: 1394094Hom.: 0 Cov.: 31 AF XY: 0.0000189 AC XY: 13AN XY: 688348
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74366
ClinVar
Submissions by phenotype
Vitamin D-dependent rickets, type 1A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2022 | Variant summary: CYP27B1 c.262delG (p.Val88TrpfsX71) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.5e-05 in 142666 control chromosomes. c.262delG has been reported in the literature in multiple individuals affected with features of Vitamin D-Dependent Rickets, Type 1 (example, Edouard_2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1998 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Val88Trpfs*71) in the CYP27B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP27B1 are known to be pathogenic (PMID: 9837822, 17488797). This variant is present in population databases (rs387906260, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with vitamin D-dependent rickets (PMID: 25086671). ClinVar contains an entry for this variant (Variation ID: 1664). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2023 | Common recurring hotspot deletion that has been reported previously in association with vitamin D-dependent rickets (VDDR type 1; also known as pseudo vitamin D deficiency rickets and vitamin D 1-alpha hydroxylase deficiency); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25086671, 1937486, 9837822, 16143014, 9844119, 35600579) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at