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rs731236

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: -2.46
Variant links:
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]

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ACMG classification

Classification made for transcript

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
VDRNM_000376.3 linkuse as main transcriptc.1056T>C p.Ile352= synonymous_variant 10/10 ENST00000549336.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VDRENST00000549336.6 linkuse as main transcriptc.1056T>C p.Ile352= synonymous_variant 10/101 NM_000376.3 P1P11473-1

Frequencies

GnomAD3 genomes
AF:
0.337
AC:
51104
AN:
151662
Hom.:
9108
Cov.:
31
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:1Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 21, 2016p.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 providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxAug 16, 2018- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Vitamin D-dependent rickets type II with alopecia Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Hepatocellular carcinoma Pathogenic:1
Likely risk allele, no assertion criteria providedcase-controlBioengineering and Technology, Gauhati UniversityJul 14, 2022- -
Periodontitis Benign:1
Benign, no assertion criteria providedcase-controlGenetics Laboratory, Lanzhou UniversityApr 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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