chr12-47889022-A-G

Variant names:

• chr12-47889022-A-G
• rs2853559
• NM_000376.3:c.-83-6248T>C

Variant summary

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

The NM_000376.3(VDR):​c.-83-6248T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 152,022 control chromosomes in the GnomAD database, including 35,853 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 0.68 (35853 hom., cov: 31)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 30 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

ENSG00000205537 (HGNC:):

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 (AFR) allele frequency at 95% confidence interval = 0.812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.-83-6248T>C		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.-83-6248T>C		intron_variant	Intron 1 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.680 AC: 103231 AN: 151904 Hom.: 35808 Cov.: 31

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.667

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

GnomAD4 genome AF: 0.680 AC: 103332 AN: 152022 Hom.: 35853 Cov.: 31 AF XY: 0.680 AC XY: 50518 AN XY: 74322

African (AFR) AF: 0.820 AC: 34025 AN: 41512

American (AMR) AF: 0.721 AC: 11028 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2349 AN: 3470

East Asian (EAS) AF: 0.674 AC: 3453 AN: 5126

South Asian (SAS) AF: 0.759 AC: 3655 AN: 4816

European-Finnish (FIN) AF: 0.585 AC: 6171 AN: 10556

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.597 AC: 40557 AN: 67940

Other (OTH) AF: 0.669 AC: 1411 AN: 2108

Alfa AF: 0.643 Hom.: 4135

Bravo AF: 0.695

Asia WGS AF: 0.723 AC: 2515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.69
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2853559; hg19: chr12-48282805;