rs11574113

Positions:

• chr12-47845117-C-G
• chr12-47845117-C-T

Variant summary

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

The NM_000376.3(VDR):​c.1025-112G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,529,098 control chromosomes in the GnomAD database, including 9,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1035 hom., cov: 29)
  • Exomes 𝑓: 0.11 (8516 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.512

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-47845117-C-G is Benign according to our data. Variant chr12-47845117-C-G is described in ClinVar as [Benign]. Clinvar id is 1182749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.1025-112G>C		intron_variant		ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.1025-112G>C		intron_variant		1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16742 AN: 151372 Hom.: 1036 Cov.: 29

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.106 AC: 145414 AN: 1377606 Hom.: 8516 AF XY: 0.105 AC XY: 72331 AN XY: 688300

Gnomad4 AFR exome AF: 0.0808

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.0818

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.0971

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.111 AC: 16743 AN: 151492 Hom.: 1035 Cov.: 29 AF XY: 0.115 AC XY: 8531 AN XY: 73978

Gnomad4 AFR AF: 0.0785

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.0767

Gnomad4 FIN AF: 0.191

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0534 Hom.: 54

Bravo AF: 0.110

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.68

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: rs11574113; hg19: chr12-48238900; COSMIC: COSV57467325;