rs3847987

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000376.3(VDR):c.*461G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 243,510 control chromosomes in the GnomAD database, including 2,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1304 hom., cov: 32)

Exomes 𝑓: 0.12 ( 764 hom. )

Consequence

VDR
NM_000376.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.62

Publications

56 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-47844285-C-A is Benign according to our data. Variant chr12-47844285-C-A is described in ClinVar as Benign. ClinVar VariationId is 308862.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3 link	c.*461G>T		3_prime_UTR_variant	Exon 10 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.*461G>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2		P11473-1

Frequencies

GnomAD3 genomes

AF:

0.123

AC:

18725

AN:

151918

Hom.:

1305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0686

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.154

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.223

Gnomad MID

AF:

0.152

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.122

GnomAD4 exome

AF:

0.119

AC:

10854

AN:

91474

Hom.:

764

Cov.:

AF XY:

0.119

AC XY:

5633

AN XY:

47498

show subpopulations

African (AFR)

AF:

0.0599

AC:

192

AN:

3204

American (AMR)

AF:

0.165

AC:

712

AN:

4308

Ashkenazi Jewish (ASJ)

AF:

0.156

AC:

343

AN:

2194

East Asian (EAS)

AF:

0.186

AC:

894

AN:

4804

South Asian (SAS)

AF:

0.0991

AC:

1156

AN:

11664

European-Finnish (FIN)

AF:

0.205

AC:

973

AN:

4738

Middle Eastern (MID)

AF:

0.108

AC:

AN:

372

European-Non Finnish (NFE)

AF:

0.107

AC:

5888

AN:

55256

Other (OTH)

AF:

0.133

AC:

656

AN:

4934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

456

912

1367

1823

2279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.123

AC:

18727

AN:

152036

Hom.:

1304

Cov.:

AF XY:

0.129

AC XY:

9569

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.0685

AC:

2841

AN:

41478

American (AMR)

AF:

0.154

AC:

2356

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

699

AN:

3468

East Asian (EAS)

AF:

0.220

AC:

1135

AN:

5160

South Asian (SAS)

AF:

0.110

AC:

530

AN:

4810

European-Finnish (FIN)

AF:

0.223

AC:

2353

AN:

10574

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8235

AN:

67958

Other (OTH)

AF:

0.121

AC:

255

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

804

1607

2411

3214

4018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.124

Hom.:

1708

Bravo

AF:

0.119

Asia WGS

AF:

0.166

AC:

577

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

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:1

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. -

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_noAF

Benign

-0.86

CADD

Benign

0.41

(source)

DANN

Benign

0.61

PhyloP100

-1.6

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over