chr12-47851452-C-A

Variant names:

• chr12-47851452-C-A
• rs7971418
• NM_000376.3:c.755+4178G>T

Variant summary

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

The NM_001364085.2(VDR):​c.755+4178G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 151,834 control chromosomes in the GnomAD database, including 21,265 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 0.53 (21265 hom., cov: 30)
• Consequence: VDR NM_001364085.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 19 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364085.2. 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.755+4178G>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.755+4178G>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.905+4178G>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.755+4178G>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.905+4178G>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.755+4178G>T		intron	N/A	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79917 AN: 151716 Hom.: 21244 Cov.: 30

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.533

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

GnomAD4 genome AF: 0.527 AC: 79991 AN: 151834 Hom.: 21265 Cov.: 30 AF XY: 0.528 AC XY: 39148 AN XY: 74198

African (AFR) AF: 0.551 AC: 22796 AN: 41386

American (AMR) AF: 0.490 AC: 7478 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2012 AN: 3466

East Asian (EAS) AF: 0.288 AC: 1485 AN: 5148

South Asian (SAS) AF: 0.569 AC: 2727 AN: 4794

European-Finnish (FIN) AF: 0.553 AC: 5835 AN: 10556

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35833 AN: 67902

Other (OTH) AF: 0.535 AC: 1130 AN: 2114

Alfa AF: 0.531 Hom.: 2750

Bravo AF: 0.520

Asia WGS AF: 0.476 AC: 1655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.031
DANN	Benign	0.48
PhyloP100		-1.2
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: rs7971418; hg19: chr12-48245235; COSMIC: COSV57467913; COSMIC: COSV57467913;