12-47846450-G-A

Variant names:

• chr12-47846450-G-A
• rs12721365
• NM_000376.3:c.909C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000376.3(VDR):​c.909C>T​(p.Ala303Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,563,288 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: VDR NM_000376.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.000006930
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.46
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-47846450-G-A is Benign according to our data. Variant chr12-47846450-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308880.
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00194 (295/152288) while in subpopulation NFE AF = 0.00318 (216/68018). AF 95% confidence interval is 0.00283. There are 1 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

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.909C>T	p.Ala303Ala	splice_region synonymous	Exon 9 of 10	NP_000367.1
	VDR	NM_001364085.2		c.909C>T	p.Ala303Ala	splice_region synonymous	Exon 9 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.1059C>T	p.Ala353Ala	splice_region synonymous	Exon 9 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.909C>T	p.Ala303Ala	splice_region synonymous	Exon 9 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.1059C>T	p.Ala353Ala	splice_region synonymous	Exon 9 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.909C>T	p.Ala303Ala	splice_region synonymous	Exon 7 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00204 AC: 350 AN: 171526 AF XY: 0.00223

Gnomad AFR exome AF: 0.000688

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00331 AC: 4677 AN: 1411000 Hom.: 10 Cov.: 32 AF XY: 0.00329 AC XY: 2292 AN XY: 697186

African (AFR) AF: 0.000497 AC: 16 AN: 32188

American (AMR) AF: 0.000597 AC: 22 AN: 36872

Ashkenazi Jewish (ASJ) AF: 0.00174 AC: 44 AN: 25288

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36814

South Asian (SAS) AF: 0.00179 AC: 144 AN: 80346

European-Finnish (FIN) AF: 0.00188 AC: 93 AN: 49480

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5690

European-Non Finnish (NFE) AF: 0.00385 AC: 4180 AN: 1085774

Other (OTH) AF: 0.00299 AC: 175 AN: 58548

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74468

African (AFR) AF: 0.000722 AC: 30 AN: 41562

American (AMR) AF: 0.00118 AC: 18 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00303 Hom.: 0

Bravo AF: 0.00171

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

May 18, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VDR: BP4, BP7

not specified Benign:2

Jul 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VDR c.909C>T (p.Ala303Ala) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 171526 control chromosomes, predominantly at a frequency of 0.0033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in VDR causing Vitamin D-Dependent Rickets Type II With Alopecia phenotype. c.909C>T has been observed in individual(s) affected with hypophosphatemia (Puente-Ruiz_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Vitamin D-Dependent Rickets Type II With Alopecia. The following publication has been ascertained in the context of this evaluation (PMID: 36999651). ClinVar contains an entry for this variant (Variation ID: 308880). Based on the evidence outlined above, the variant was classified as benign.

Nov 07, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Vitamin D-dependent rickets type II with alopecia Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.065
DANN	Benign	0.49
PhyloP100		-1.5
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000069
dbscSNV1_RF	Benign	0.0020
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: rs12721365; hg19: chr12-48240233;