rs2238139

Positions:

• chr12-47862497-G-A
• chr12-47862497-G-C
• chr12-47862497-G-T

Variant summary

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

The NM_000376.3(VDR):​c.277+2550C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.794 in 152,212 control chromosomes in the GnomAD database, including 48,194 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 0.79 (48194 hom., cov: 33)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.392

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.277+2550C>T		intron_variant		ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.277+2550C>T		intron_variant		1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120805 AN: 152094 Hom.: 48155 Cov.: 33

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.691

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.797

Gnomad OTH AF: 0.797

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

GnomAD4 genome AF: 0.794 AC: 120902 AN: 152212 Hom.: 48194 Cov.: 33 AF XY: 0.797 AC XY: 59335 AN XY: 74416

Gnomad4 AFR AF: 0.780

Gnomad4 AMR AF: 0.731

Gnomad4 ASJ AF: 0.691

Gnomad4 EAS AF: 0.957

Gnomad4 SAS AF: 0.834

Gnomad4 FIN AF: 0.868

Gnomad4 NFE AF: 0.797

Gnomad4 OTH AF: 0.799

Alfa AF: 0.765 Hom.: 2437

Bravo AF: 0.783

Asia WGS AF: 0.902 AC: 3136 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.71

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: rs2238139; hg19: chr12-48256280;