12-47857011-T-A

Variant names:

• chr12-47857011-T-A
• rs11574085
• NM_000376.3:c.583+118A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.583+118A>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.583+118A>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.733+118A>T		intron	N/A	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.583+118A>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.733+118A>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.583+118A>T		intron	N/A	ENSP00000229022.5

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

African (AFR) AF: 0.00741 AC: 229 AN: 30904

American (AMR) AF: 0.0232 AC: 1005 AN: 43356

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2519 AN: 24266

East Asian (EAS) AF: 0.000104 AC: 4 AN: 38322

South Asian (SAS) AF: 0.0513 AC: 4194 AN: 81792

European-Finnish (FIN) AF: 0.0258 AC: 1299 AN: 50430

Middle Eastern (MID) AF: 0.0454 AC: 182 AN: 4006

European-Non Finnish (NFE) AF: 0.0635 AC: 64641 AN: 1018108

Other (OTH) AF: 0.0542 AC: 3037 AN: 56032

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

African (AFR) AF: 0.0105 AC: 438 AN: 41560

American (AMR) AF: 0.0350 AC: 535 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 400 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0547 AC: 264 AN: 4822

European-Finnish (FIN) AF: 0.0237 AC: 252 AN: 10620

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0599 AC: 4071 AN: 68008

Other (OTH) AF: 0.0364 AC: 77 AN: 2114

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

Oct 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.55
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11574085; hg19: chr12-48250794;