rs11168267

chr12-47857759-G-Achr12-47857759-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000376.3(VDR):c.278-71C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0919 in 1,557,362 control chromosomes in the GnomAD database, including 7,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.093 (723 hom., cov: 32)
  • Exomes 𝑓: 0.092 (6493 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-47857759-G-A is Benign according to our data. Variant chr12-47857759-G-A is described in ClinVar as [Benign]. Clinvar id is 1252969.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.278-71C>T		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.278-71C>T		intron_variant		1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14166 AN: 152020 Hom.: 721 Cov.: 32

Gnomad AFR AF: 0.0701

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.0900

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.0793

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0902

Gnomad OTH AF: 0.0899

GnomAD4 exome AF: 0.0918 AC: 128952 AN: 1405224 Hom.: 6493 AF XY: 0.0915 AC XY: 63749 AN XY: 696918

Gnomad4 AFR exome AF: 0.0731

Gnomad4 AMR exome AF: 0.0957

Gnomad4 ASJ exome AF: 0.0880

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.0829

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.0859

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.0931 AC: 14171 AN: 152138 Hom.: 723 Cov.: 32 AF XY: 0.0961 AC XY: 7150 AN XY: 74384

Gnomad4 AFR AF: 0.0701

Gnomad4 AMR AF: 0.0899

Gnomad4 ASJ AF: 0.0812

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.0902

Gnomad4 OTH AF: 0.0885

Alfa AF: 0.0914 Hom.: 145

Bravo AF: 0.0901

Asia WGS AF: 0.140 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.25
Dann	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs11168267; hg19: chr12-48251542; COSMIC: COSV57467987;