chr12-47943286-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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]

VDR Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395324.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000395324.6	TSL:5	c.-507C>T		upstream_gene	N/A	ENSP00000378734.2	P11473-1

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

African (AFR) AF: 0.258 AC: 10717 AN: 41520

American (AMR) AF: 0.146 AC: 2239 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 586 AN: 3472

East Asian (EAS) AF: 0.287 AC: 1480 AN: 5164

South Asian (SAS) AF: 0.0653 AC: 315 AN: 4826

European-Finnish (FIN) AF: 0.124 AC: 1314 AN: 10624

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.145 AC: 9863 AN: 67998

Other (OTH) AF: 0.182 AC: 385 AN: 2114

Alfa AF: 0.159 Hom.: 3992

Bravo AF: 0.184

Asia WGS AF: 0.157 AC: 546 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		0.085
PromoterAI		0.050	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4073729; hg19: chr12-48337069;