rs2228570
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_000376.3(VDR):c.2T>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).
Frequency
Genomes: not found (cov: 30)
Consequence
VDR
NM_000376.3 start_lost
NM_000376.3 start_lost
Scores
7
7
3
Clinical Significance
Conservation
PhyloP100: 4.35
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VDR | NM_000376.3 | c.2T>G | p.Met1? | start_lost | 3/10 | ENST00000549336.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VDR | ENST00000549336.6 | c.2T>G | p.Met1? | start_lost | 3/10 | 1 | NM_000376.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
Cov.:
30
GnomAD4 exome Cov.: 69
GnomAD4 exome
Cov.:
69
GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Vitamin D-dependent rickets type II with alopecia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | FAHD UNIT, Department of Genetics, King Faisal Specialist Hospital and Research Centre | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;T;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;T;.;D;.
Polyphen
D;D;D;.;.;.;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);.;Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);Gain of solvent accessibility (P = 0.11);
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
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