chr12-47901568-T-C

Variant names:

• chr12-47901568-T-C
• rs12721377
• NM_000376.3:c.-84+3387A>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.-84+3387A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 155,508 control chromosomes in the GnomAD database, including 56 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 0.022 (48 hom., cov: 33)
  • Exomes 𝑓: 0.049 (8 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• Publications: 11 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

ENSG00000205537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0685 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.-84+3387A>G		intron	N/A	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.-84+3387A>G		intron	N/A	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.67+2996A>G		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.-84+3387A>G		intron	N/A	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.67+2996A>G		intron	N/A	ENSP00000447173.1	P11473-2
	VDR	ENST00000395324.6	TSL:5	c.-83-18794A>G		intron	N/A	ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3404 AN: 152234 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0730

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0296

GnomAD4 exome AF: 0.0488 AC: 154 AN: 3156 Hom.: 8 Cov.: 0 AF XY: 0.0446 AC XY: 72 AN XY: 1614

African (AFR) AF: 0.0676 AC: 5 AN: 74

American (AMR) AF: 0.0625 AC: 1 AN: 16

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.0658 AC: 5 AN: 76

European-Finnish (FIN) AF: 0.00938 AC: 7 AN: 746

Middle Eastern (MID) AF: 0.0803 AC: 116 AN: 1444

European-Non Finnish (NFE) AF: 0.0338 AC: 14 AN: 414

Other (OTH) AF: 0.0160 AC: 6 AN: 376

GnomAD4 genome AF: 0.0223 AC: 3400 AN: 152352 Hom.: 48 Cov.: 33 AF XY: 0.0223 AC XY: 1665 AN XY: 74518

African (AFR) AF: 0.0209 AC: 868 AN: 41582

American (AMR) AF: 0.0211 AC: 323 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0730 AC: 253 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4830

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10628

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1561 AN: 68034

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0223 Hom.: 20

Bravo AF: 0.0226

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.8
DANN	Benign	0.42
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism

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: rs12721377; hg19: chr12-48295351;