12-47902182-T-C

Variant names:

• chr12-47902182-T-C
• rs10083198
• NM_000376.3:c.-84+2773A>G

Variant summary

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

The NM_000376.3(VDR):​c.-84+2773A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 152,162 control chromosomes in the GnomAD database, including 17,400 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 0.43 (17400 hom., cov: 33)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526

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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.-84+2773A>G		intron_variant	Intron 1 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.-84+2773A>G		intron_variant	Intron 1 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65199 AN: 152044 Hom.: 17372 Cov.: 33

Gnomad AFR AF: 0.750

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.410

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

GnomAD4 genome AF: 0.429 AC: 65264 AN: 152162 Hom.: 17400 Cov.: 33 AF XY: 0.425 AC XY: 31646 AN XY: 74378

Gnomad4 AFR AF: 0.750

Gnomad4 AMR AF: 0.288

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.543

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.405

Alfa AF: 0.235 Hom.: 892

Bravo AF: 0.445

Asia WGS AF: 0.477 AC: 1657 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.82

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: rs10083198; hg19: chr12-48295965;