12-47857759-G-A

Variant names:

• chr12-47857759-G-A
• rs11168267
• NM_000376.3:c.278-71C>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.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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.15
• Publications: 30 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=-0.86).
• BP6: Variant 12-47857759-G-A is Benign according to our data. Variant chr12-47857759-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.193 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.278-71C>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.278-71C>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.428-71C>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.278-71C>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.428-71C>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.278-71C>T		intron	N/A	ENSP00000229022.5

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

African (AFR) AF: 0.0731 AC: 2373 AN: 32480

American (AMR) AF: 0.0957 AC: 4115 AN: 43008

Ashkenazi Jewish (ASJ) AF: 0.0880 AC: 2145 AN: 24366

East Asian (EAS) AF: 0.201 AC: 7881 AN: 39148

South Asian (SAS) AF: 0.0829 AC: 6749 AN: 81428

European-Finnish (FIN) AF: 0.147 AC: 6840 AN: 46470

Middle Eastern (MID) AF: 0.126 AC: 566 AN: 4498

European-Non Finnish (NFE) AF: 0.0859 AC: 92419 AN: 1075534

Other (OTH) AF: 0.101 AC: 5864 AN: 58292

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

African (AFR) AF: 0.0701 AC: 2909 AN: 41512

American (AMR) AF: 0.0899 AC: 1374 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 282 AN: 3472

East Asian (EAS) AF: 0.203 AC: 1048 AN: 5160

South Asian (SAS) AF: 0.0798 AC: 384 AN: 4812

European-Finnish (FIN) AF: 0.148 AC: 1569 AN: 10600

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0902 AC: 6132 AN: 67986

Other (OTH) AF: 0.0885 AC: 187 AN: 2114

Alfa AF: 0.0935 Hom.: 222

Bravo AF: 0.0901

Asia WGS AF: 0.140 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 11, 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	-0.86
CADD	Benign	0.25
DANN	Benign	0.43
PhyloP100		-1.2
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: rs11168267; hg19: chr12-48251542; COSMIC: COSV57467987;