rs2283343

Variant names:

• chr12-47860995-G-A
• rs2283343
• NM_000376.3:c.278-3307C>T

Variant summary

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

The NM_000376.3(VDR):​c.278-3307C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 152,168 control chromosomes in the GnomAD database, including 17,696 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 0.48 (17696 hom., cov: 34)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 5 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.278-3307C>T		intron_variant	Intron 4 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.278-3307C>T		intron_variant	Intron 4 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72850 AN: 152050 Hom.: 17683 Cov.: 34

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.485

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

GnomAD4 genome AF: 0.479 AC: 72900 AN: 152168 Hom.: 17696 Cov.: 34 AF XY: 0.479 AC XY: 35635 AN XY: 74384

African (AFR) AF: 0.460 AC: 19086 AN: 41502

American (AMR) AF: 0.446 AC: 6816 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.488 AC: 1693 AN: 3472

East Asian (EAS) AF: 0.318 AC: 1650 AN: 5186

South Asian (SAS) AF: 0.462 AC: 2231 AN: 4826

European-Finnish (FIN) AF: 0.531 AC: 5615 AN: 10578

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34135 AN: 68002

Other (OTH) AF: 0.486 AC: 1027 AN: 2114

Alfa AF: 0.491 Hom.: 2349

Bravo AF: 0.469

Asia WGS AF: 0.438 AC: 1521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.58
DANN	Benign	0.26
PhyloP100		-0.21
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: rs2283343; hg19: chr12-48254778;