rs3847987

Variant names:

• chr12-47844285-C-A
• rs3847987
• NM_000376.3:c.*461G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000376.3(VDR):​c.*461G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 243,510 control chromosomes in the GnomAD database, including 2,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1304 hom., cov: 32)
  • Exomes 𝑓: 0.12 (764 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.62
• Publications: 56 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-47844285-C-A is Benign according to our data. Variant chr12-47844285-C-A is described in ClinVar as Benign. ClinVar VariationId is 308862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 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.*461G>T		3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.*260G>T		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*461G>T		3_prime_UTR	Exon 10 of 10	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.*461G>T		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.*461G>T		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1	P11473-2
	VDR	ENST00000229022.9	TSL:5	c.*260G>T		3_prime_UTR	Exon 8 of 8	ENSP00000229022.5	A0A5K1VW50

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18725 AN: 151918 Hom.: 1305 Cov.: 32

Gnomad AFR AF: 0.0686

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.122

GnomAD4 exome AF: 0.119 AC: 10854 AN: 91474 Hom.: 764 Cov.: 0 AF XY: 0.119 AC XY: 5633 AN XY: 47498

African (AFR) AF: 0.0599 AC: 192 AN: 3204

American (AMR) AF: 0.165 AC: 712 AN: 4308

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 343 AN: 2194

East Asian (EAS) AF: 0.186 AC: 894 AN: 4804

South Asian (SAS) AF: 0.0991 AC: 1156 AN: 11664

European-Finnish (FIN) AF: 0.205 AC: 973 AN: 4738

Middle Eastern (MID) AF: 0.108 AC: 40 AN: 372

European-Non Finnish (NFE) AF: 0.107 AC: 5888 AN: 55256

Other (OTH) AF: 0.133 AC: 656 AN: 4934

GnomAD4 genome AF: 0.123 AC: 18727 AN: 152036 Hom.: 1304 Cov.: 32 AF XY: 0.129 AC XY: 9569 AN XY: 74306

African (AFR) AF: 0.0685 AC: 2841 AN: 41478

American (AMR) AF: 0.154 AC: 2356 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 699 AN: 3468

East Asian (EAS) AF: 0.220 AC: 1135 AN: 5160

South Asian (SAS) AF: 0.110 AC: 530 AN: 4810

European-Finnish (FIN) AF: 0.223 AC: 2353 AN: 10574

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8235 AN: 67958

Other (OTH) AF: 0.121 AC: 255 AN: 2112

Alfa AF: 0.124 Hom.: 1708

Bravo AF: 0.119

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Periodontitis (1)
-	-	1	Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.41
DANN	Benign	0.61
PhyloP100		-1.6
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: rs3847987; hg19: chr12-48238068;