12-47879112-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PVS1_SupportingBP6BA1

The NM_001364085.2(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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.63 ( 288010 hom. )

Consequence

VDR
NM_001364085.2 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:11

Conservation

PhyloP100: 4.35

Publications

1392 publications found

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 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

VDR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 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 0.007 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 Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308887.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364085.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VDR	NM_000376.3	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 3 of 10	NP_000367.1
VDR	NM_001364085.2		c.2T>C	p.Met1?	start_lost	Exon 3 of 10	NP_001351014.1
VDR	NM_001017535.2		c.2T>C	p.Met1?	start_lost	Exon 4 of 11	NP_001017535.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VDR	ENST00000549336.6	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 3 of 10	ENSP00000449573.2
VDR	ENST00000550325.5	TSL:1	c.152T>C	p.Met51Thr	missense	Exon 3 of 10	ENSP00000447173.1
VDR	ENST00000229022.9	TSL:5	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	ENSP00000229022.5

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

GnomAD2 exomes

AF:

0.629

AC:

157889

AN:

250932

AF XY:

0.638

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 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

African (AFR)

AF:

0.790

AC:

26461

AN:

33478

American (AMR)

AF:

0.535

AC:

23904

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.561

AC:

14665

AN:

26130

East Asian (EAS)

AF:

0.591

AC:

23470

AN:

39692

South Asian (SAS)

AF:

0.766

AC:

66066

AN:

86250

European-Finnish (FIN)

AF:

0.634

AC:

33805

AN:

53312

Middle Eastern (MID)

AF:

0.732

AC:

4208

AN:

5748

European-Non Finnish (NFE)

AF:

0.614

AC:

682991

AN:

1111940

Other (OTH)

AF:

0.636

AC:

38411

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

19722

39444

59166

78888

98610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18458

36916

55374

73832

92290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.662

AC:

100529

AN:

151824

Hom.:

33907

Cov.:

AF XY:

0.663

AC XY:

49215

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.780

AC:

32265

AN:

41358

American (AMR)

AF:

0.578

AC:

8823

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.572

AC:

1981

AN:

3466

East Asian (EAS)

AF:

0.570

AC:

2926

AN:

5136

South Asian (SAS)

AF:

0.739

AC:

3558

AN:

4814

European-Finnish (FIN)

AF:

0.644

AC:

6774

AN:

10518

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.616

AC:

41877

AN:

67950

Other (OTH)

AF:

0.689

AC:

1452

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1677

3355

5032

6710

8387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

802

1604

2406

3208

4010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.623

Hom.:

74405

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

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Vitamin D-dependent rickets type II with alopecia (5)

not specified (4)

not provided (2)

Periodontitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0000083

MetaSVM

Benign

-0.93

PhyloP100

4.4

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.36

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

0.29

Vest4

0.34

MPC

0.57

ClinPred

0.096

GERP RS

2.9

PromoterAI

0.076

Neutral

(source)

Varity_R

0.69

gMVP

0.35

Mutation Taster

=138/62

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over