12-47878678-G-A

Position:

• chr12-47878678-G-A

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.146+290C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 493,084 control chromosomes in the GnomAD database, including 1,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (395 hom., cov: 32)
  • Exomes 𝑓: 0.056 (638 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.738

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=-0.89).
• BP6: Variant 12-47878678-G-A is Benign according to our data. Variant chr12-47878678-G-A is described in ClinVar as [Benign]. Clinvar id is 1231146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.146+290C>T		intron_variant		ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.146+290C>T		intron_variant		1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 10178 AN: 152110 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0930

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0699

GnomAD4 exome AF: 0.0565 AC: 19248 AN: 340856 Hom.: 638 AF XY: 0.0549 AC XY: 10317 AN XY: 187996

Gnomad4 AFR exome AF: 0.0931

Gnomad4 AMR exome AF: 0.0711

Gnomad4 ASJ exome AF: 0.0291

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.0461

Gnomad4 FIN exome AF: 0.0680

Gnomad4 NFE exome AF: 0.0506

Gnomad4 OTH exome AF: 0.0597

GnomAD4 genome AF: 0.0670 AC: 10194 AN: 152228 Hom.: 395 Cov.: 32 AF XY: 0.0672 AC XY: 5002 AN XY: 74422

Gnomad4 AFR AF: 0.0930

Gnomad4 AMR AF: 0.0664

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.0513

Gnomad4 FIN AF: 0.0618

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0335 Hom.: 31

Bravo AF: 0.0704

Asia WGS AF: 0.101 AC: 354 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	Oct 16, 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	-0.89
CADD	Benign	1.1
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11574050; hg19: chr12-48272461;