12-47908762-C-T

Variant names:

• chr12-47908762-C-T
• rs11568820
• ENST00000395324.6:c.-83-25988G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000395324.6(VDR):​c.-83-25988G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 152,090 control chromosomes in the GnomAD database, including 16,359 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 0.38 (16359 hom., cov: 31)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203
• Publications: 346 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: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 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.-83-25988G>A		intron_variant	Intron 1 of 9	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57431 AN: 151972 Hom.: 16322 Cov.: 31

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.354

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

GnomAD4 genome AF: 0.378 AC: 57511 AN: 152090 Hom.: 16359 Cov.: 31 AF XY: 0.373 AC XY: 27764 AN XY: 74342

African (AFR) AF: 0.801 AC: 33220 AN: 41492

American (AMR) AF: 0.233 AC: 3560 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3472

East Asian (EAS) AF: 0.422 AC: 2176 AN: 5162

South Asian (SAS) AF: 0.322 AC: 1550 AN: 4810

European-Finnish (FIN) AF: 0.155 AC: 1634 AN: 10564

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13535 AN: 67984

Other (OTH) AF: 0.351 AC: 741 AN: 2114

Alfa AF: 0.276 Hom.: 18627

Bravo AF: 0.403

Asia WGS AF: 0.386 AC: 1341 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.92
DANN	Benign	0.17
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs11568820; hg19: chr12-48302545;