12-47869181-G-A

Variant names:

• chr12-47869181-G-A
• rs886441
• NM_000376.3:c.147-4004C>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.147-4004C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 152,140 control chromosomes in the GnomAD database, including 43,406 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 0.75 (43406 hom., cov: 32)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 44 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.147-4004C>T		intron	N/A	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.147-4004C>T		intron	N/A	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.297-4004C>T		intron	N/A	NP_001017536.1	P11473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.147-4004C>T		intron	N/A	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.297-4004C>T		intron	N/A	ENSP00000447173.1	P11473-2
	VDR	ENST00000229022.9	TSL:5	c.147-4004C>T		intron	N/A	ENSP00000229022.5	A0A5K1VW50

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113708 AN: 152022 Hom.: 43395 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.875

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.762

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

GnomAD4 genome AF: 0.748 AC: 113761 AN: 152140 Hom.: 43406 Cov.: 32 AF XY: 0.752 AC XY: 55925 AN XY: 74360

African (AFR) AF: 0.599 AC: 24808 AN: 41444

American (AMR) AF: 0.708 AC: 10828 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2431 AN: 3472

East Asian (EAS) AF: 0.955 AC: 4951 AN: 5182

South Asian (SAS) AF: 0.834 AC: 4027 AN: 4826

European-Finnish (FIN) AF: 0.875 AC: 9282 AN: 10606

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54929 AN: 68004

Other (OTH) AF: 0.765 AC: 1616 AN: 2112

Alfa AF: 0.786 Hom.: 213958

Bravo AF: 0.727

Asia WGS AF: 0.878 AC: 3052 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.94
DANN	Benign	0.40
PhyloP100		-0.027
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: rs886441; hg19: chr12-48262964;