12-47911861-A-G

Variant names:

• chr12-47911861-A-G
• rs4077869
• ENST00000395324.6:c.-83-29087T>C

Variant summary

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

The ENST00000395324.6(VDR):​c.-83-29087T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 152,190 control chromosomes in the GnomAD database, including 4,353 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 0.14 (4353 hom., cov: 32)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• Publications: 4 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=-0.65).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 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.-83-29087T>C		intron_variant	Intron 1 of 9	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20646 AN: 152072 Hom.: 4334 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0610

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.0906

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.0998

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

GnomAD4 genome AF: 0.136 AC: 20709 AN: 152190 Hom.: 4353 Cov.: 32 AF XY: 0.133 AC XY: 9932 AN XY: 74436

African (AFR) AF: 0.450 AC: 18662 AN: 41460

American (AMR) AF: 0.0609 AC: 931 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.0517 AC: 268 AN: 5186

South Asian (SAS) AF: 0.0913 AC: 441 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68026

Other (OTH) AF: 0.0992 AC: 210 AN: 2116

Alfa AF: 0.0941 Hom.: 398

Bravo AF: 0.154

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		2.2
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: rs4077869; hg19: chr12-48305644;