rs11574114

chr12-47845100-C-T

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.1025-95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,580,452 control chromosomes in the GnomAD database, including 2,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.072 (627 hom., cov: 29)
  • Exomes 𝑓: 0.040 (1451 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.20

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=-0.88).
• BP6: Variant 12-47845100-C-T is Benign according to our data. Variant chr12-47845100-C-T is described in ClinVar as [Benign]. Clinvar id is 1251714.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.1025-95G>A		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.1025-95G>A		intron_variant		1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 10799 AN: 151186 Hom.: 621 Cov.: 29

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0603

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00333

Gnomad SAS AF: 0.0438

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0723

GnomAD4 exome AF: 0.0397 AC: 56806 AN: 1429148 Hom.: 1451 AF XY: 0.0396 AC XY: 28218 AN XY: 712236

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0392

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.00162

Gnomad4 SAS exome AF: 0.0420

Gnomad4 FIN exome AF: 0.0610

Gnomad4 NFE exome AF: 0.0365

Gnomad4 OTH exome AF: 0.0450

GnomAD4 genome AF: 0.0716 AC: 10829 AN: 151304 Hom.: 627 Cov.: 29 AF XY: 0.0712 AC XY: 5261 AN XY: 73918

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0601

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00353

Gnomad4 SAS AF: 0.0436

Gnomad4 FIN AF: 0.0620

Gnomad4 NFE AF: 0.0370

Gnomad4 OTH AF: 0.0711

Alfa AF: 0.0618 Hom.: 61

Bravo AF: 0.0762

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 18, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.50
Dann	Benign	0.37

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: rs11574114; hg19: chr12-48238883;