rs7975232

Positions:

• chr12-47845054-C-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.1025-49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,600,160 control chromosomes in the GnomAD database, including 225,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23205 hom., cov: 29)
  • Exomes 𝑓: 0.53 (202307 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:4
• Conservation: PhyloP100: -0.874

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=-0.78).
• BP6: Variant 12-47845054-C-A is Benign according to our data. Variant chr12-47845054-C-A is described in ClinVar as [Benign]. Clinvar id is 1252227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.1025-49G>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.1025-49G>T		intron_variant		1	NM_000376.3	ENSP00000449573	P1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 82955 AN: 151104 Hom.: 23182 Cov.: 29

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.550

GnomAD3 exomes AF: 0.511 AC: 123050 AN: 240798 Hom.: 32488 AF XY: 0.518 AC XY: 67861 AN XY: 130972

Gnomad AFR exome AF: 0.626

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.556

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.525 AC: 761265 AN: 1448938 Hom.: 202307 Cov.: 47 AF XY: 0.528 AC XY: 380601 AN XY: 721232

Gnomad4 AFR exome AF: 0.637

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.567

Gnomad4 EAS exome AF: 0.306

Gnomad4 SAS exome AF: 0.576

Gnomad4 FIN exome AF: 0.552

Gnomad4 NFE exome AF: 0.527

Gnomad4 OTH exome AF: 0.531

GnomAD4 genome AF: 0.549 AC: 83031 AN: 151222 Hom.: 23205 Cov.: 29 AF XY: 0.549 AC XY: 40532 AN XY: 73840

Gnomad4 AFR AF: 0.627

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.583

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.559

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.528

Gnomad4 OTH AF: 0.552

Alfa AF: 0.554 Hom.: 6048

Bravo AF: 0.545

Asia WGS AF: 0.468 AC: 1628 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	- -

Hepatocellular carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Bioengineering and Technology, Gauhati University

Jul 14, 2022

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Periodontitis Benign:1

Benign, no assertion criteria provided

case-control

Genetics Laboratory, Lanzhou University

Apr 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.5
DANN	Benign	0.84

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: rs7975232; hg19: chr12-48238837; COSMIC: COSV57467972;