rs10875708

Variant names:

• chr12-47939967-A-G
• rs10875708
• ENST00000395324.6:c.-84+2896T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-47939967-A-G
• chr12-47939967-A-T

Variant summary

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

The ENST00000395324.6(VDR):​c.-84+2896T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,226 control chromosomes in the GnomAD database, including 3,756 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 0.21 (3756 hom., cov: 32)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 4 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000395324.6	c.-84+2896T>C		intron_variant	Intron 1 of 9	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32697 AN: 152108 Hom.: 3758 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.229

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

GnomAD4 genome AF: 0.215 AC: 32704 AN: 152226 Hom.: 3756 Cov.: 32 AF XY: 0.214 AC XY: 15962 AN XY: 74420

African (AFR) AF: 0.254 AC: 10541 AN: 41530

American (AMR) AF: 0.170 AC: 2604 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 757 AN: 3470

East Asian (EAS) AF: 0.385 AC: 1990 AN: 5170

South Asian (SAS) AF: 0.214 AC: 1031 AN: 4828

European-Finnish (FIN) AF: 0.188 AC: 1992 AN: 10576

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13162 AN: 68024

Other (OTH) AF: 0.226 AC: 478 AN: 2116

Alfa AF: 0.198 Hom.: 1844

Bravo AF: 0.215

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.34
DANN	Benign	0.58
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10875708; hg19: chr12-48333750;