rs12717991

chr12-47865343-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.147-166G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 152,022 control chromosomes in the GnomAD database, including 10,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.37 (10932 hom., cov: 32)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.33

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=-0.97).
• BP6: Variant 12-47865343-C-T is Benign according to our data. Variant chr12-47865343-C-T is described in ClinVar as [Benign]. Clinvar id is 1258255.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.68 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.147-166G>A		intron_variant		ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.147-166G>A		intron_variant		1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56505 AN: 151904 Hom.: 10929 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.347

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.364

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.372 AC: 56536 AN: 152022 Hom.: 10932 Cov.: 32 AF XY: 0.376 AC XY: 27943 AN XY: 74314

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.699

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.365

Alfa AF: 0.371 Hom.: 3594

Bravo AF: 0.362

Asia WGS AF: 0.497 AC: 1729 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

Aug 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.066
Dann	Benign	0.42

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: rs12717991; hg19: chr12-48259126; COSMIC: COSV57468730;