12-47844184-T-G

Position:

• chr12-47844184-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000376.3(VDR):​c.*562A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 167,906 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (111 hom., cov: 32)
  • Exomes 𝑓: 0.029 (6 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.884

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-47844184-T-G is Benign according to our data. Variant chr12-47844184-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 882526.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0324 (4926/152106) while in subpopulation AMR AF= 0.0466 (712/15280). AF 95% confidence interval is 0.0438. There are 111 homozygotes in gnomad4. There are 2533 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 111 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.*562A>C		3_prime_UTR_variant	10/10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336	c.*562A>C		3_prime_UTR_variant	10/10	1	NM_000376.3	ENSP00000449573.2
VDR	ENST00000550325	c.*562A>C		3_prime_UTR_variant	10/10	1		ENSP00000447173.1
VDR	ENST00000229022	c.*361A>C		3_prime_UTR_variant	8/8	5		ENSP00000229022.5
VDR	ENST00000395324	c.*562A>C		3_prime_UTR_variant	10/10	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4927 AN: 151988 Hom.: 110 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0633

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0421

GnomAD4 exome AF: 0.0288 AC: 455 AN: 15800 Hom.: 6 Cov.: 0 AF XY: 0.0288 AC XY: 232 AN XY: 8058

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.0327

Gnomad4 ASJ exome AF: 0.0180

Gnomad4 EAS exome AF: 0.00645

Gnomad4 SAS exome AF: 0.0194

Gnomad4 FIN exome AF: 0.0479

Gnomad4 NFE exome AF: 0.0314

Gnomad4 OTH exome AF: 0.0407

GnomAD4 genome AF: 0.0324 AC: 4926 AN: 152106 Hom.: 111 Cov.: 32 AF XY: 0.0341 AC XY: 2533 AN XY: 74362

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.0450

Gnomad4 FIN AF: 0.0633

Gnomad4 NFE AF: 0.0369

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0215 Hom.: 9

Bravo AF: 0.0302

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.19
DANN	Benign	0.47

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: rs3858733; hg19: chr12-48237967;