NM_000376.3:c.756-3968C>T

Variant names:

• chr12-47850776-G-A
• rs2239185
• NM_000376.3:c.756-3968C>T

Variant summary

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

The NM_000376.3(VDR):​c.756-3968C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 151,440 control chromosomes in the GnomAD database, including 21,682 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 (21682 hom., cov: 31)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 53 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.566 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.756-3968C>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.756-3968C>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.906-3968C>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.756-3968C>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.906-3968C>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.756-3968C>T		intron	N/A	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.533 AC: 80604 AN: 151318 Hom.: 21654 Cov.: 31

Gnomad AFR AF: 0.572

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.538

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

GnomAD4 genome AF: 0.533 AC: 80688 AN: 151440 Hom.: 21682 Cov.: 31 AF XY: 0.533 AC XY: 39432 AN XY: 73976

African (AFR) AF: 0.572 AC: 23605 AN: 41246

American (AMR) AF: 0.493 AC: 7505 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2019 AN: 3470

East Asian (EAS) AF: 0.286 AC: 1475 AN: 5152

South Asian (SAS) AF: 0.569 AC: 2729 AN: 4796

European-Finnish (FIN) AF: 0.554 AC: 5802 AN: 10474

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35736 AN: 67786

Other (OTH) AF: 0.539 AC: 1131 AN: 2100

Alfa AF: 0.523 Hom.: 37331

Bravo AF: 0.527

Asia WGS AF: 0.477 AC: 1659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.61
PhyloP100		-1.1
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: rs2239185; hg19: chr12-48244559;