rs121909801
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_000376.3(VDR):c.88C>T(p.Arg30Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000186 in 1,613,814 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
VDR
NM_000376.3 stop_gained
NM_000376.3 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.90
Genes affected
VDR (HGNC:12679): (vitamin D receptor) This gene encodes vitamin D3 receptor, which is a member of the nuclear hormone receptor superfamily of ligand-inducible transcription factors. This receptor also functions as a receptor for the secondary bile acid, lithocholic acid. Downstream targets of vitamin D3 receptor are principally involved in mineral metabolism, though this receptor regulates a variety of other metabolic pathways, such as those involved in immune response and cancer. Mutations in this gene are associated with type II vitamin D-resistant rickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Jun 2018]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 34 pathogenic variants in the truncated region.
PP5
Variant 12-47879026-G-A is Pathogenic according to our data. Variant chr12-47879026-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7757.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VDR | NM_000376.3 | c.88C>T | p.Arg30Ter | stop_gained | 3/10 | ENST00000549336.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VDR | ENST00000549336.6 | c.88C>T | p.Arg30Ter | stop_gained | 3/10 | 1 | NM_000376.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152160
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250926Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135700
GnomAD3 exomes
AF:
AC:
4
AN:
250926
Hom.:
AF XY:
AC XY:
2
AN XY:
135700
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461654Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16AN XY: 727140
GnomAD4 exome
AF:
AC:
29
AN:
1461654
Hom.:
Cov.:
30
AF XY:
AC XY:
16
AN XY:
727140
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
GnomAD4 genome
AF:
AC:
1
AN:
152160
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74328
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
ExAC
AF:
AC:
1
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Vitamin D-dependent rickets type II with alopecia Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Sep 01, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with VDR-related disorder (ClinVar ID: VCV000007757 / PMID: 9360557). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1998 | - - |
Uncertain significance, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | FAHD UNIT, Department of Genetics, King Faisal Specialist Hospital and Research Centre | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg30*) in the VDR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VDR are known to be pathogenic (PMID: 10204116, 24246681). This variant is present in population databases (rs121909801, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with vitamin D-dependent rickets (PMID: 9360557, 19049339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7757). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at