chr12-47844974-A-G

Variant names:

• chr12-47844974-A-G
• rs731236
• NM_000376.3:c.1056T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000376.3(VDR):​c.1056T>C​(p.Ile352Ile) 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:9
• Conservation: PhyloP100: -2.46
• Publications: 1136 publications found

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]

VDR Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 308877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.1056T>C	p.Ile352Ile	synonymous	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.1056T>C	p.Ile352Ile	synonymous	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.1206T>C	p.Ile402Ile	synonymous	Exon 10 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.1056T>C	p.Ile352Ile	synonymous	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.1206T>C	p.Ile402Ile	synonymous	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.1056T>C	p.Ile352Ile	synonymous	Exon 8 of 8	ENSP00000229022.5

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

GnomAD2 exomes AF: 0.327 AC: 82106 AN: 250982 AF XY: 0.337

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 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

African (AFR) AF: 0.280 AC: 9378 AN: 33478

American (AMR) AF: 0.224 AC: 10004 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 9362 AN: 26130

East Asian (EAS) AF: 0.0849 AC: 3371 AN: 39684

South Asian (SAS) AF: 0.347 AC: 29930 AN: 86258

European-Finnish (FIN) AF: 0.332 AC: 17601 AN: 53050

Middle Eastern (MID) AF: 0.412 AC: 2367 AN: 5746

European-Non Finnish (NFE) AF: 0.401 AC: 445934 AN: 1111970

Other (OTH) AF: 0.357 AC: 21563 AN: 60380

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

African (AFR) AF: 0.286 AC: 11842 AN: 41388

American (AMR) AF: 0.303 AC: 4611 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1243 AN: 3466

East Asian (EAS) AF: 0.0622 AC: 320 AN: 5142

South Asian (SAS) AF: 0.330 AC: 1585 AN: 4810

European-Finnish (FIN) AF: 0.330 AC: 3479 AN: 10530

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26940 AN: 67886

Other (OTH) AF: 0.350 AC: 738 AN: 2106

Alfa AF: 0.375 Hom.: 33940

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hepatocellular carcinoma Pathogenic:1

Jul 14, 2022

Bioengineering and Technology, Gauhati University

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: case-control

Periodontitis Benign:1

Apr 20, 2023

Genetics Laboratory, Lanzhou University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.030
DANN	Benign	0.49
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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