rs7976091

Variant names:

• chr12-47910769-C-T
• rs7976091
• ENST00000395324.6:c.-83-27995G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000395324.6(VDR):​c.-83-27995G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 152,192 control chromosomes in the GnomAD database, including 16,205 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 0.38 (16205 hom., cov: 33)
• Consequence: VDR ENST00000395324.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531
• Publications: 14 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.789 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.-83-27995G>A		intron_variant	Intron 1 of 9	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57256 AN: 152074 Hom.: 16169 Cov.: 33

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.377 AC: 57334 AN: 152192 Hom.: 16205 Cov.: 33 AF XY: 0.372 AC XY: 27661 AN XY: 74394

African (AFR) AF: 0.796 AC: 33060 AN: 41530

American (AMR) AF: 0.232 AC: 3554 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2177 AN: 5164

South Asian (SAS) AF: 0.321 AC: 1548 AN: 4826

European-Finnish (FIN) AF: 0.154 AC: 1633 AN: 10598

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13528 AN: 67982

Other (OTH) AF: 0.349 AC: 739 AN: 2116

Alfa AF: 0.259 Hom.: 1369

Bravo AF: 0.401

Asia WGS AF: 0.387 AC: 1346 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		0.53
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: rs7976091; hg19: chr12-48304552;