12-47870045-G-T

Variant names:

• chr12-47870045-G-T
• rs2189480
• NM_000376.3:c.147-4868C>A

Variant summary

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

The NM_000376.3(VDR):​c.147-4868C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,976 control chromosomes in the GnomAD database, including 10,375 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 0.37 (10375 hom., cov: 32)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.628
• Publications: 78 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.147-4868C>A		intron_variant	Intron 3 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.147-4868C>A		intron_variant	Intron 3 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55707 AN: 151858 Hom.: 10377 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.633

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.367 AC: 55725 AN: 151976 Hom.: 10375 Cov.: 32 AF XY: 0.366 AC XY: 27160 AN XY: 74294

African (AFR) AF: 0.348 AC: 14411 AN: 41462

American (AMR) AF: 0.334 AC: 5096 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1159 AN: 3468

East Asian (EAS) AF: 0.632 AC: 3267 AN: 5168

South Asian (SAS) AF: 0.347 AC: 1668 AN: 4810

European-Finnish (FIN) AF: 0.361 AC: 3817 AN: 10564

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25206 AN: 67928

Other (OTH) AF: 0.363 AC: 765 AN: 2106

Alfa AF: 0.359 Hom.: 20056

Bravo AF: 0.366

Asia WGS AF: 0.462 AC: 1607 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.58
PhyloP100		0.63
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: rs2189480; hg19: chr12-48263828;