rs4303288

chr12-47942836-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000395324.6(VDR):c.-84+27T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 149,642 control chromosomes in the GnomAD database, including 27,030 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.60 (26821 hom., cov: 25)
  • Exomes 𝑓: 0.59 (209 hom.)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000395324.6	c.-84+27T>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 89001 AN: 148458 Hom.: 26788 Cov.: 25

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.558

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.573

GnomAD4 exome AF: 0.593 AC: 632 AN: 1066 Hom.: 209 Cov.: 0 AF XY: 0.586 AC XY: 429 AN XY: 732

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.667

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.474

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.591

GnomAD4 genome AF: 0.600 AC: 89085 AN: 148576 Hom.: 26821 Cov.: 25 AF XY: 0.603 AC XY: 43682 AN XY: 72406

Gnomad4 AFR AF: 0.553

Gnomad4 AMR AF: 0.671

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.529

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.660

Gnomad4 NFE AF: 0.604

Gnomad4 OTH AF: 0.578

Alfa AF: 0.598 Hom.: 3391

Bravo AF: 0.598

Asia WGS AF: 0.620 AC: 2151 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	1.5
Dann	Benign	0.23

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4303288; hg19: chr12-48336619;