rs731236

chr12-47844974-A-Gchr12-47844974-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000376.3(VDR):c.1056T>C(p.Ile352=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,613,190 control chromosomes in the GnomAD database, including 115,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9106 hom., cov: 31)
  • Exomes 𝑓: 0.38 (106762 hom.)
• Consequence: VDR NM_000376.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:8
• Conservation: PhyloP100: -2.46

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-47844974-A-G is Benign according to our data. Variant chr12-47844974-A-G is described in ClinVar as [Benign]. Clinvar id is 308877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47844974-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.1056T>C	p.Ile352=	synonymous_variant	10/10	ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.1056T>C	p.Ile352=	synonymous_variant	10/10	1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51104 AN: 151662 Hom.: 9108 Cov.: 31

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.0619

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.349

GnomAD3 exomes AF: 0.327 AC: 82106 AN: 250982 Hom.: 14891 AF XY: 0.337 AC XY: 45658 AN XY: 135678

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.213

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.0540

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.330

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.376 AC: 549510 AN: 1461414 Hom.: 106762 Cov.: 71 AF XY: 0.376 AC XY: 273622 AN XY: 727036

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.358

Gnomad4 EAS exome AF: 0.0849

Gnomad4 SAS exome AF: 0.347

Gnomad4 FIN exome AF: 0.332

Gnomad4 NFE exome AF: 0.401

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.337 AC: 51113 AN: 151776 Hom.: 9106 Cov.: 31 AF XY: 0.332 AC XY: 24617 AN XY: 74150

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.0622

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.330

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.350

Alfa AF: 0.385 Hom.: 15813

Bravo AF: 0.327

Asia WGS AF: 0.220 AC: 765 AN: 3478

EpiCase AF: 0.406

EpiControl AF: 0.402

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ile352Ile in exon 11 of VDR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 39.88% (26601/66704) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs731236). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	- -

Vitamin D-dependent rickets type II with alopecia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

Hepatocellular carcinoma Pathogenic:1

Likely risk allele, no assertion criteria provided

case-control

Bioengineering and Technology, Gauhati University

Jul 14, 2022

- -

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	-0.86
CADD	Benign	0.030
DANN	Benign	0.49

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: rs731236; hg19: chr12-48238757; COSMIC: COSV57469256;