12-47844974-A-G

Position:

chr12-47844974-A-G

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

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:9

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]

VDR links:

Genome browser will be placed here

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	Protein	UniProt
VDR	NM_000376.3 linkuse as main transcript	c.1056T>C	p.Ile352=	synonymous_variant	10/10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6 linkuse as main transcript	c.1056T>C	p.Ile352=	synonymous_variant	10/10	1	NM_000376.3	ENSP00000449573	P1	P11473-1

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51104

AN:

151662

Hom.:

9108

Cov.:

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.:

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.:

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Vitamin D-dependent rickets type II with alopecia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
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. -

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over