12-47899933-G-T

Variant names:

• chr12-47899933-G-T
• rs11168293
• NM_000376.3:c.-84+5022C>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.-84+5022C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 984,234 control chromosomes in the GnomAD database, including 52,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6256 hom., cov: 32)
  • Exomes 𝑓: 0.33 (46243 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.175
• Publications: 22 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

ENSG00000205537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 12-47899933-G-T is Benign according to our data. Variant chr12-47899933-G-T is described in ClinVar as Benign. ClinVar VariationId is 308891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.341 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.-84+5022C>A		intron	N/A	NP_000367.1
	VDR	NM_001017535.2		c.-180C>A		5_prime_UTR	Exon 2 of 11	NP_001017535.1
	VDR	NM_001374661.1		c.-99C>A		5_prime_UTR	Exon 2 of 10	NP_001361590.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.-84+5022C>A		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.67+4631C>A		intron	N/A	ENSP00000447173.1
	VDR	ENST00000546653.5	TSL:5	c.-99C>A		5_prime_UTR	Exon 2 of 7	ENSP00000448659.1

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40908 AN: 152046 Hom.: 6246 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.329 AC: 274022 AN: 832070 Hom.: 46243 Cov.: 30 AF XY: 0.330 AC XY: 126976 AN XY: 384318

African (AFR) AF: 0.139 AC: 2198 AN: 15758

American (AMR) AF: 0.264 AC: 259 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1536 AN: 5146

East Asian (EAS) AF: 0.0346 AC: 130 AN: 3762

South Asian (SAS) AF: 0.187 AC: 3072 AN: 16446

European-Finnish (FIN) AF: 0.400 AC: 112 AN: 280

Middle Eastern (MID) AF: 0.301 AC: 487 AN: 1616

European-Non Finnish (NFE) AF: 0.340 AC: 258514 AN: 760824

Other (OTH) AF: 0.283 AC: 7714 AN: 27256

GnomAD4 genome AF: 0.269 AC: 40949 AN: 152164 Hom.: 6256 Cov.: 32 AF XY: 0.269 AC XY: 20038 AN XY: 74376

African (AFR) AF: 0.152 AC: 6315 AN: 41526

American (AMR) AF: 0.260 AC: 3981 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1000 AN: 3470

East Asian (EAS) AF: 0.0206 AC: 107 AN: 5184

South Asian (SAS) AF: 0.184 AC: 888 AN: 4828

European-Finnish (FIN) AF: 0.403 AC: 4262 AN: 10576

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23431 AN: 67972

Other (OTH) AF: 0.268 AC: 566 AN: 2112

Alfa AF: 0.308 Hom.: 11888

Bravo AF: 0.253

Asia WGS AF: 0.143 AC: 496 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Vitamin D-dependent rickets type II with alopecia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.17
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: rs11168293; hg19: chr12-48293716; COSMIC: COSV57470224;