rs7975232

Variant names:

• chr12-47845054-C-A
• rs7975232
• NM_000376.3:c.1025-49G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001364085.2(VDR):​c.1025-49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,600,160 control chromosomes in the GnomAD database, including 225,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.55 (23205 hom., cov: 29)
  • Exomes 𝑓: 0.53 (202307 hom.)
• Consequence: VDR NM_001364085.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: -0.874
• Publications: 945 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-47845054-C-A is Benign according to our data. Variant chr12-47845054-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1252227.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.62 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.1025-49G>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.1025-49G>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.1175-49G>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.1025-49G>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.1175-49G>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.1025-49G>T		intron	N/A	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.549 AC: 82955 AN: 151104 Hom.: 23182 Cov.: 29

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.511 AC: 123050 AN: 240798 AF XY: 0.518

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.278

Gnomad FIN exome AF: 0.556

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.525 AC: 761265 AN: 1448938 Hom.: 202307 Cov.: 47 AF XY: 0.528 AC XY: 380601 AN XY: 721232

African (AFR) AF: 0.637 AC: 21267 AN: 33410

American (AMR) AF: 0.423 AC: 18914 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 14800 AN: 26114

East Asian (EAS) AF: 0.306 AC: 12120 AN: 39658

South Asian (SAS) AF: 0.576 AC: 49603 AN: 86130

European-Finnish (FIN) AF: 0.552 AC: 23584 AN: 42686

Middle Eastern (MID) AF: 0.624 AC: 2765 AN: 4428

European-Non Finnish (NFE) AF: 0.527 AC: 586253 AN: 1111688

Other (OTH) AF: 0.531 AC: 31959 AN: 60138

GnomAD4 genome AF: 0.549 AC: 83031 AN: 151222 Hom.: 23205 Cov.: 29 AF XY: 0.549 AC XY: 40532 AN XY: 73840

African (AFR) AF: 0.627 AC: 25779 AN: 41136

American (AMR) AF: 0.504 AC: 7672 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2021 AN: 3468

East Asian (EAS) AF: 0.290 AC: 1464 AN: 5046

South Asian (SAS) AF: 0.559 AC: 2685 AN: 4806

European-Finnish (FIN) AF: 0.550 AC: 5740 AN: 10430

Middle Eastern (MID) AF: 0.555 AC: 162 AN: 292

European-Non Finnish (NFE) AF: 0.528 AC: 35812 AN: 67814

Other (OTH) AF: 0.552 AC: 1162 AN: 2106

Alfa AF: 0.536 Hom.: 41243

Bravo AF: 0.545

Asia WGS AF: 0.468 AC: 1628 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	1	Vitamin D-dependent rickets type II with alopecia (2)
1	-	-	Hepatocellular carcinoma (1)
-	-	1	Periodontitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.5
DANN	Benign	0.84
PhyloP100		-0.87
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: rs7975232; hg19: chr12-48238837; COSMIC: COSV57467972;