12-47879112-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PVS1_SupportingBP6_Very_StrongBA1

The NM_000376.3(VDR):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.629 in 1,613,468 control chromosomes in the GnomAD database, including 321,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33907 hom., cov: 30)

Exomes 𝑓: 0.63 ( 288010 hom. )

Consequence

VDR
NM_000376.3 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:10

Conservation

PhyloP100: 4.35

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 -15 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 4 codons. Genomic position: 47879104. Lost 0.008 part of the original CDS.

BP6

Variant 12-47879112-A-G is Benign according to our data. Variant chr12-47879112-A-G is described in ClinVar as [Benign]. Clinvar id is 308887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-47879112-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3 link	c.2T>C	p.Met1?	start_lost	Exon 3 of 10	ENST00000549336.6	NP_000367.1	P11473-1F1D8P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6 link	c.2T>C	p.Met1?	start_lost	Exon 3 of 10	1	NM_000376.3	ENSP00000449573.2		P11473-1

Frequencies

GnomAD3 genomes

AF:

0.662

AC:

100424

AN:

151702

Hom.:

33864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.780

Gnomad AMI

AF:

0.737

Gnomad AMR

AF:

0.578

Gnomad ASJ

AF:

0.572

Gnomad EAS

AF:

0.570

Gnomad SAS

AF:

0.739

Gnomad FIN

AF:

0.644

Gnomad MID

AF:

0.703

Gnomad NFE

AF:

0.616

Gnomad OTH

AF:

0.690

GnomAD3 exomes

AF:

0.629

AC:

157889

AN:

250932

Hom.:

50640

AF XY:

0.638

AC XY:

86520

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.788

Gnomad AMR exome

AF:

0.526

Gnomad ASJ exome

AF:

0.565

Gnomad EAS exome

AF:

0.543

Gnomad SAS exome

AF:

0.768

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.619

Gnomad OTH exome

AF:

0.640

GnomAD4 exome

AF:

0.625

AC:

913981

AN:

1461644

Hom.:

288010

Cov.:

AF XY:

0.630

AC XY:

457818

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.790

Gnomad4 AMR exome

AF:

0.535

Gnomad4 ASJ exome

AF:

0.561

Gnomad4 EAS exome

AF:

0.591

Gnomad4 SAS exome

AF:

0.766

Gnomad4 FIN exome

AF:

0.634

Gnomad4 NFE exome

AF:

0.614

Gnomad4 OTH exome

AF:

0.636

GnomAD4 genome

AF:

0.662

AC:

100529

AN:

151824

Hom.:

33907

Cov.:

AF XY:

0.663

AC XY:

49215

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.780

Gnomad4 AMR

AF:

0.578

Gnomad4 ASJ

AF:

0.572

Gnomad4 EAS

AF:

0.570

Gnomad4 SAS

AF:

0.739

Gnomad4 FIN

AF:

0.644

Gnomad4 NFE

AF:

0.616

Gnomad4 OTH

AF:

0.689

Alfa

AF:

0.611

Hom.:

44694

Bravo

AF:

0.660

TwinsUK

AF:

0.600

AC:

2225

ALSPAC

AF:

0.627

AC:

2416

ESP6500AA

AF:

0.788

AC:

3474

ESP6500EA

AF:

0.614

AC:

5281

ExAC

AF:

0.637

AC:

77320

Asia WGS

AF:

0.633

AC:

2198

AN:

3478

EpiCase

AF:

0.631

EpiControl

AF:

0.630

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vitamin D-dependent rickets type II with alopecia

Pathogenic:1Benign:4

Mar 06, 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

- -

Mar 07, 2022

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Feb 17, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error, the reference base (c.152T) is the minor allele. This a llele (T) has been identified in 48% (5540/11550) of Latino chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs22285 70) and thus meets the criteria to be classified as benign. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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:2

Aug 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16019132, 12807755, 20473893, 18752562, 19131500, 15899948, 21283672, 21814771, 18763633, 9169350, 23855914, 30092343, 27939971, 21820934, 29506625, 22181683, 23286944, 24078452, 24702903, 24771013, 27683185) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T;T;.;T;T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;.;D;T;D;D;D

MetaRNN

Benign

0.0000083

T;T;T;T;T;T;T

MetaSVM

Benign

-0.93

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.36

N;N;N;N;N;N;N

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;T;.;D;.

Polyphen

0.29

B;B;B;.;.;.;.

Vest4

0.34

MPC

0.57

ClinPred

0.096

GERP RS

2.9

Varity_R

0.69

gMVP

0.35

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