rs4303288

Variant names:

• chr12-47942836-A-C
• rs4303288
• ENST00000395324.6:c.-84+27T>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+27T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 149,642 control chromosomes in the GnomAD database, including 27,030 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 0.60 (26821 hom., cov: 25)
  • Exomes 𝑓: 0.59 (209 hom.)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.338
• Publications: 8 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.66 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+27T>G		intron	N/A	ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes AF: 0.600 AC: 89001 AN: 148458 Hom.: 26788 Cov.: 25

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.699

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.528

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.558

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.573

GnomAD4 exome AF: 0.593 AC: 632 AN: 1066 Hom.: 209 Cov.: 0 AF XY: 0.586 AC XY: 429 AN XY: 732

African (AFR) AF: 0.700 AC: 7 AN: 10

American (AMR) AF: 0.667 AC: 8 AN: 12

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.300 AC: 6 AN: 20

South Asian (SAS) AF: 0.474 AC: 18 AN: 38

European-Finnish (FIN) AF: 0.662 AC: 200 AN: 302

Middle Eastern (MID) AF: 1.00 AC: 6 AN: 6

European-Non Finnish (NFE) AF: 0.568 AC: 358 AN: 630

Other (OTH) AF: 0.591 AC: 26 AN: 44

GnomAD4 genome AF: 0.600 AC: 89085 AN: 148576 Hom.: 26821 Cov.: 25 AF XY: 0.603 AC XY: 43682 AN XY: 72406

African (AFR) AF: 0.553 AC: 22216 AN: 40142

American (AMR) AF: 0.671 AC: 10022 AN: 14944

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2066 AN: 3438

East Asian (EAS) AF: 0.529 AC: 2605 AN: 4928

South Asian (SAS) AF: 0.639 AC: 2973 AN: 4656

European-Finnish (FIN) AF: 0.660 AC: 6726 AN: 10190

Middle Eastern (MID) AF: 0.562 AC: 163 AN: 290

European-Non Finnish (NFE) AF: 0.604 AC: 40496 AN: 67028

Other (OTH) AF: 0.578 AC: 1192 AN: 2064

Alfa AF: 0.598 Hom.: 3391

Bravo AF: 0.598

Asia WGS AF: 0.620 AC: 2151 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.5
DANN	Benign	0.23
PhyloP100		0.34
PromoterAI		-0.050	Neutral
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: rs4303288;

hg19: chr12-48336619;