12-47878492-T-C

Variant names:

• chr12-47878492-T-C
• rs11168275
• NM_000376.3:c.146+476A>G

Variant summary

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

The NM_000376.3(VDR):​c.146+476A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,140 control chromosomes in the GnomAD database, including 6,820 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 0.29 (6820 hom., cov: 32)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.882
• Publications: 32 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 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.146+476A>G		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.146+476A>G		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.296+476A>G		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.146+476A>G		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.296+476A>G		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.146+476A>G		intron	N/A	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43994 AN: 152022 Hom.: 6809 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.281

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

GnomAD4 genome AF: 0.290 AC: 44056 AN: 152140 Hom.: 6820 Cov.: 32 AF XY: 0.291 AC XY: 21608 AN XY: 74378

African (AFR) AF: 0.340 AC: 14103 AN: 41502

American (AMR) AF: 0.290 AC: 4427 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 896 AN: 3466

East Asian (EAS) AF: 0.582 AC: 3006 AN: 5168

South Asian (SAS) AF: 0.416 AC: 2007 AN: 4822

European-Finnish (FIN) AF: 0.209 AC: 2209 AN: 10594

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16458 AN: 67998

Other (OTH) AF: 0.284 AC: 597 AN: 2102

Alfa AF: 0.262 Hom.: 9034

Bravo AF: 0.299

Asia WGS AF: 0.459 AC: 1595 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.46
PhyloP100		-0.88
Mutation Taster		=99/1	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: rs11168275; hg19: chr12-48272275;