12-47857750-C-T

Variant names:

• chr12-47857750-C-T
• rs11168266
• NM_000376.3:c.278-62G>A

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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.300
• Publications: 27 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=-0.83).
• BP6: Variant 12-47857750-C-T is Benign according to our data. Variant chr12-47857750-C-T is described in ClinVar as Benign. ClinVar VariationId is 1247454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.569 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.278-62G>A		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.278-62G>A		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.428-62G>A		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.278-62G>A		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.428-62G>A		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.278-62G>A		intron	N/A	ENSP00000229022.5

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

African (AFR) AF: 0.589 AC: 19407 AN: 32976

American (AMR) AF: 0.437 AC: 19131 AN: 43764

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 13426 AN: 25192

East Asian (EAS) AF: 0.324 AC: 12726 AN: 39292

South Asian (SAS) AF: 0.526 AC: 44114 AN: 83904

European-Finnish (FIN) AF: 0.615 AC: 30341 AN: 49360

Middle Eastern (MID) AF: 0.655 AC: 3209 AN: 4898

European-Non Finnish (NFE) AF: 0.552 AC: 603393 AN: 1093516

Other (OTH) AF: 0.546 AC: 32265 AN: 59140

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

African (AFR) AF: 0.575 AC: 23840 AN: 41426

American (AMR) AF: 0.518 AC: 7904 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1864 AN: 3466

East Asian (EAS) AF: 0.320 AC: 1647 AN: 5148

South Asian (SAS) AF: 0.509 AC: 2442 AN: 4802

European-Finnish (FIN) AF: 0.615 AC: 6469 AN: 10526

Middle Eastern (MID) AF: 0.575 AC: 168 AN: 292

European-Non Finnish (NFE) AF: 0.554 AC: 37641 AN: 67958

Other (OTH) AF: 0.571 AC: 1203 AN: 2106

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.42
DANN	Benign	0.85
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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