rs11168266

chr12-47857750-C-T

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.278-62G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 1,583,932 control chromosomes in the GnomAD database, including 236,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (23441 hom., cov: 31)
  • Exomes 𝑓: 0.54 (213311 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.300

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=-0.83).
• BP6: Variant 12-47857750-C-T is Benign according to our data. Variant chr12-47857750-C-T is described in ClinVar as [Benign]. Clinvar id is 1247454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.278-62G>A		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.278-62G>A		intron_variant		1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.551 AC: 83655 AN: 151772 Hom.: 23417 Cov.: 31

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.598

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.538

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.571

GnomAD4 exome AF: 0.543 AC: 778012 AN: 1432042 Hom.: 213311 AF XY: 0.544 AC XY: 386263 AN XY: 710258

Gnomad4 AFR exome AF: 0.589

Gnomad4 AMR exome AF: 0.437

Gnomad4 ASJ exome AF: 0.533

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.526

Gnomad4 FIN exome AF: 0.615

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.546

GnomAD4 genome AF: 0.551 AC: 83722 AN: 151890 Hom.: 23441 Cov.: 31 AF XY: 0.550 AC XY: 40853 AN XY: 74214

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.320

Gnomad4 SAS AF: 0.509

Gnomad4 FIN AF: 0.615

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.571

Alfa AF: 0.557 Hom.: 2925

Bravo AF: 0.543

Asia WGS AF: 0.475 AC: 1650 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

Aug 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.42
Dann	Benign	0.85

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: rs11168266; hg19: chr12-48251533; COSMIC: COSV57467331;