rs12721377

chr12-47901568-T-C

Variant summary

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

The NM_000376.3(VDR):c.-84+3387A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 155,508 control chromosomes in the GnomAD database, including 56 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 0.022 (48 hom., cov: 33)
  • Exomes 𝑓: 0.049 (8 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.-84+3387A>G		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.-84+3387A>G		intron_variant		1	NM_000376.3	P1
	ENST00000380601.2			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3404 AN: 152234 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0730

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.0488 AC: 154 AN: 3156 Hom.: 8 Cov.: 0 AF XY: 0.0446 AC XY: 72 AN XY: 1614

Gnomad4 AFR exome AF: 0.0676

Gnomad4 AMR exome AF: 0.0625

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0658

Gnomad4 FIN exome AF: 0.00938

Gnomad4 NFE exome AF: 0.0338

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0223 AC: 3400 AN: 152352 Hom.: 48 Cov.: 33 AF XY: 0.0223 AC XY: 1665 AN XY: 74518

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0211

Gnomad4 ASJ AF: 0.0730

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0487

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0231 Hom.: 10

Bravo AF: 0.0226

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	6.8
Dann	Benign	0.42

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

Other links and lift over

dbSNP: rs12721377; hg19: chr12-48295351;