rs11574085

Positions:

• chr12-47857011-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000376.3(VDR):​c.583+118A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 1,499,514 control chromosomes in the GnomAD database, including 2,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (157 hom., cov: 32)
  • Exomes 𝑓: 0.057 (2584 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.519

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-47857011-T-A is Benign according to our data. Variant chr12-47857011-T-A is described in ClinVar as [Benign]. Clinvar id is 1220995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.583+118A>T		intron_variant		ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.583+118A>T		intron_variant		1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6076 AN: 152180 Hom.: 157 Cov.: 32

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0543

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0599

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.0572 AC: 77110 AN: 1347216 Hom.: 2584 AF XY: 0.0576 AC XY: 38784 AN XY: 673130

Gnomad4 AFR exome AF: 0.00741

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.000104

Gnomad4 SAS exome AF: 0.0513

Gnomad4 FIN exome AF: 0.0258

Gnomad4 NFE exome AF: 0.0635

Gnomad4 OTH exome AF: 0.0542

GnomAD4 genome AF: 0.0399 AC: 6077 AN: 152298 Hom.: 157 Cov.: 32 AF XY: 0.0387 AC XY: 2881 AN XY: 74470

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0547

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0599

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0441 Hom.: 21

Bravo AF: 0.0386

Asia WGS AF: 0.0200 AC: 71 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.55

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: rs11574085; hg19: chr12-48250794;