rs2525044

chr12-47848473-A-Gchr12-47848473-A-T

Variant summary

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

The NM_000376.3(VDR):c.756-1665T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 150,216 control chromosomes in the GnomAD database, including 30,372 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 0.63 (30372 hom., cov: 28)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.756-1665T>C		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.756-1665T>C		intron_variant		1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.627 AC: 94093 AN: 150102 Hom.: 30325 Cov.: 28

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.571

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.633

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.624

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

GnomAD4 genome AF: 0.627 AC: 94198 AN: 150216 Hom.: 30372 Cov.: 28 AF XY: 0.628 AC XY: 45932 AN XY: 73180

Gnomad4 AFR AF: 0.787

Gnomad4 AMR AF: 0.571

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.612

Gnomad4 FIN AF: 0.633

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.624

Alfa AF: 0.600 Hom.: 5978

Bravo AF: 0.622

Asia WGS AF: 0.514 AC: 1789 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.077
Dann	Benign	0.17

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: rs2525044; hg19: chr12-48242256;