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GeneBe

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

Scores

7
6
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.35
Variant links:
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
VDRNM_000376.3 linkuse as main transcriptc.2T>G p.Met1? start_lost 3/10 ENST00000549336.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VDRENST00000549336.6 linkuse as main transcriptc.2T>G p.Met1? start_lost 3/101 NM_000376.3 P1P11473-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
69
GnomAD4 genome
Cov.:
30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Benign
0.35
T;T;T;.;T;T;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.82
D
MutationTaster
Benign
1.0
D;D;N;N;N
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.19
N;N;N;N;N;N;N
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;T;.;D;.
Polyphen
0.97
D;D;D;.;.;.;.
Vest4
0.74
MutPred
0.98
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
0.93
MPC
1.5
ClinPred
0.99
D
GERP RS
2.9
Varity_R
0.88
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2228570; hg19: chr12-48272895; API