rs11574129

chr12-47843520-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000376.3(VDR):c.*1226T>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 0.0173 in 152,290 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (86 hom., cov: 31)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.755

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=-0.94).
• BP6: Variant 12-47843520-A-G is Benign according to our data. Variant chr12-47843520-A-G is described in ClinVar as [Benign]. Clinvar id is 308851.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-47843520-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.*1226T>C		3_prime_UTR_variant	10/10	ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.*1226T>C		3_prime_UTR_variant	10/10	1	NM_000376.3	P1
VDR	ENST00000550325.5	c.*1226T>C		3_prime_UTR_variant	10/10	1
VDR	ENST00000229022.9	c.*1025T>C		3_prime_UTR_variant	8/8	5
VDR	ENST00000395324.6	c.*1226T>C		3_prime_UTR_variant	10/10	5		P1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2628 AN: 151878 Hom.: 86 Cov.: 31

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.00997

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0136 AC: 4 AN: 294 Hom.: 0 Cov.: 0 AF XY: 0.0165 AC XY: 3 AN XY: 182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00735

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0173 AC: 2626 AN: 151996 Hom.: 86 Cov.: 31 AF XY: 0.0198 AC XY: 1468 AN XY: 74306

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.154

Gnomad4 SAS AF: 0.00998

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0115 Hom.: 16

Bravo AF: 0.0172

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 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	-0.94
Cadd	Benign	0.45
Dann	Benign	0.34

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: rs11574129; hg19: chr12-48237303;