chr12-47922478-T-C

Variant names:

• chr12-47922478-T-C
• rs10459217
• ENST00000395324.6:c.-84+20385A>G

Variant summary

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

The ENST00000395324.6(VDR):​c.-84+20385A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,112 control chromosomes in the GnomAD database, including 4,473 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 0.23 (4473 hom., cov: 32)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443
• Publications: 6 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.35 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.-84+20385A>G		intron	N/A	ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35269 AN: 151994 Hom.: 4471 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.232 AC: 35289 AN: 152112 Hom.: 4473 Cov.: 32 AF XY: 0.232 AC XY: 17255 AN XY: 74378

African (AFR) AF: 0.312 AC: 12917 AN: 41466

American (AMR) AF: 0.170 AC: 2599 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 731 AN: 3470

East Asian (EAS) AF: 0.364 AC: 1882 AN: 5174

South Asian (SAS) AF: 0.230 AC: 1112 AN: 4826

European-Finnish (FIN) AF: 0.187 AC: 1980 AN: 10590

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13358 AN: 67998

Other (OTH) AF: 0.236 AC: 498 AN: 2112

Alfa AF: 0.207 Hom.: 471

Bravo AF: 0.234

Asia WGS AF: 0.286 AC: 993 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	6.9
DANN	Benign	0.35
PhyloP100		0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10459217;

hg19: chr12-48316261;