12-47914391-A-G

Position:

• chr12-47914391-A-G

Variant summary

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

The ENST00000395324.6(VDR):​c.-84+28472T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 152,102 control chromosomes in the GnomAD database, including 18,413 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 0.41 (18413 hom., cov: 31)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.45

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000395324.6	c.-84+28472T>C		intron_variant		5		ENSP00000378734	P1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61604 AN: 151984 Hom.: 18366 Cov.: 31

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.406 AC: 61691 AN: 152102 Hom.: 18413 Cov.: 31 AF XY: 0.403 AC XY: 29940 AN XY: 74372

Gnomad4 AFR AF: 0.833

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.287

Gnomad4 EAS AF: 0.552

Gnomad4 SAS AF: 0.413

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.214

Gnomad4 OTH AF: 0.378

Alfa AF: 0.254 Hom.: 10748

Bravo AF: 0.430

Asia WGS AF: 0.468 AC: 1628 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.27
DANN	Benign	0.42

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7970314; hg19: chr12-48308174;