12-47894463-G-A

Variant names:

• chr12-47894463-G-A
• rs11574026
• NM_000376.3:c.-84+10492C>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.-84+10492C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0772 in 152,322 control chromosomes in the GnomAD database, including 631 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 0.077 (631 hom., cov: 33)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 18 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.118 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.-84+10492C>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.-84+10492C>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.67+10101C>T		intron	N/A	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.-84+10492C>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.67+10101C>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000395324.6	TSL:5	c.-83-11689C>T		intron	N/A	ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.0772 AC: 11753 AN: 152204 Hom.: 630 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.0855

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

GnomAD4 genome AF: 0.0772 AC: 11754 AN: 152322 Hom.: 631 Cov.: 33 AF XY: 0.0746 AC XY: 5554 AN XY: 74488

African (AFR) AF: 0.0213 AC: 885 AN: 41576

American (AMR) AF: 0.0688 AC: 1053 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 351 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4830

European-Finnish (FIN) AF: 0.0884 AC: 938 AN: 10608

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8166 AN: 68020

Other (OTH) AF: 0.0851 AC: 180 AN: 2116

Alfa AF: 0.105 Hom.: 695

Bravo AF: 0.0749

Asia WGS AF: 0.0160 AC: 54 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.58
PhyloP100		-0.40
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: rs11574026; hg19: chr12-48288246;