12-47844184-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000376.3(VDR):c.*562A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 167,906 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.032 ( 111 hom., cov: 32)

Exomes 𝑓: 0.029 ( 6 hom. )

Consequence

VDR
NM_000376.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.884

Publications

10 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 12-47844184-T-G is Benign according to our data. Variant chr12-47844184-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 882526.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0324 (4926/152106) while in subpopulation AMR AF = 0.0466 (712/15280). AF 95% confidence interval is 0.0438. There are 111 homozygotes in GnomAd4. There are 2533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 111 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3 link	c.*562A>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000549336.6	NP_000367.1	P11473-1F1D8P8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
VDR	ENST00000549336.6 link	c.*562A>C	3_prime_UTR_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2	P11473-1
VDR	ENST00000550325.5 link	c.*562A>C	3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000447173.1	P11473-2
VDR	ENST00000229022.9 link	c.*361A>C	3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000229022.5	A0A5K1VW50
VDR	ENST00000395324.6 link	c.*562A>C	3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes

AF:

0.0324

AC:

4927

AN:

151988

Hom.:

110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0467

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00290

Gnomad SAS

AF:

0.0451

Gnomad FIN

AF:

0.0633

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0369

Gnomad OTH

AF:

0.0421

GnomAD4 exome

AF:

0.0288

AC:

455

AN:

15800

Hom.:

Cov.:

AF XY:

0.0288

AC XY:

232

AN XY:

8058

show subpopulations

African (AFR)

AF:

0.0189

AC:

AN:

370

American (AMR)

AF:

0.0327

AC:

AN:

2508

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

AN:

222

East Asian (EAS)

AF:

0.00645

AC:

AN:

1240

South Asian (SAS)

AF:

0.0194

AC:

AN:

1550

European-Finnish (FIN)

AF:

0.0479

AC:

AN:

376

Middle Eastern (MID)

AF:

0.0294

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0314

AC:

277

AN:

8812

Other (OTH)

AF:

0.0407

AC:

AN:

688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0324

AC:

4926

AN:

152106

Hom.:

111

Cov.:

AF XY:

0.0341

AC XY:

2533

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0141

AC:

585

AN:

41506

American (AMR)

AF:

0.0466

AC:

712

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0219

AC:

AN:

3472

East Asian (EAS)

AF:

0.00310

AC:

AN:

5166

South Asian (SAS)

AF:

0.0450

AC:

217

AN:

4826

European-Finnish (FIN)

AF:

0.0633

AC:

670

AN:

10592

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0369

AC:

2506

AN:

67948

Other (OTH)

AF:

0.0417

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

243

486

728

971

1214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0298

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vitamin D-dependent rickets type II with alopecia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.19

(source)

DANN

Benign

0.47

PhyloP100

-0.88

Mutation Taster

=100/0

polymorphism

(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