chr12-47899933-G-T

Variant names:

• chr12-47899933-G-T
• rs11168293
• NM_000376.3:c.-84+5022C>A

Variant summary

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

The NM_001017535.2(VDR):​c.-180C>A variant causes a 5 prime UTR 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_001017535.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.175

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]

ENSG00000205537 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.-84+5022C>A		intron_variant	Intron 1 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.-84+5022C>A		intron_variant	Intron 1 of 9	1	NM_000376.3	ENSP00000449573.2

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

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.400

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.283

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

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.260

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.0206

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.345

Gnomad4 OTH AF: 0.268

Alfa AF: 0.310 Hom.: 8194

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.64

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: rs11168293; hg19: chr12-48293716; COSMIC: COSV57470224;