rs4073729

Variant names:

• chr12-47943286-G-A
• rs4073729
• ENST00000395324.6:c.-507C>T

Variant summary

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

The ENST00000395324.6(VDR):​c.-507C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,232 control chromosomes in the GnomAD database, including 2,724 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 0.18 (2724 hom., cov: 33)
• Consequence: VDR ENST00000395324.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850

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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000395324.6	c.-507C>T		upstream_gene_variant		5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27001 AN: 152114 Hom.: 2723 Cov.: 33

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.185

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.177 AC: 27007 AN: 152232 Hom.: 2724 Cov.: 33 AF XY: 0.174 AC XY: 12935 AN XY: 74442

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.287

Gnomad4 SAS AF: 0.0653

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.182

Alfa AF: 0.159 Hom.: 580

Bravo AF: 0.184

Asia WGS AF: 0.157 AC: 546 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.85

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4073729; hg19: chr12-48337069;