Genetic Variant NM_000376.3:c.*437C>G (chr12-47844309-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000376.3(VDR):c.*437C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0352 in 278,398 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 131 hom., cov: 32)

Exomes 𝑓: 0.035 ( 100 hom. )

Consequence

VDR
NM_000376.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.906

Publications

7 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: G2P, Labcorp Genetics (formerly Invitae)
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=-0.83).

BP6

Variant 12-47844309-G-C is Benign according to our data. Variant chr12-47844309-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 308863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.035 (5325/152262) while in subpopulation AMR AF = 0.0505 (772/15296). AF 95% confidence interval is 0.0475. There are 131 homozygotes in GnomAd4. There are 2707 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 131 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VDR	NM_000376.3	MANE Select	c.*437C>G	3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
VDR	NM_001364085.2		c.*236C>G	3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
VDR	NM_001017536.2		c.*437C>G	3_prime_UTR	Exon 10 of 10	NP_001017536.1	P11473-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VDR	ENST00000549336.6	TSL:1 MANE Select	c.*437C>G	3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
VDR	ENST00000550325.5	TSL:1	c.*437C>G	3_prime_UTR	Exon 10 of 10	ENSP00000447173.1	P11473-2
VDR	ENST00000229022.9	TSL:5	c.*236C>G	3_prime_UTR	Exon 8 of 8	ENSP00000229022.5	A0A5K1VW50

Frequencies

GnomAD3 genomes

AF:

0.0350

AC:

5326

AN:

152144

Hom.:

130

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.0407

Gnomad AMR

AF:

0.0506

Gnomad ASJ

AF:

0.0233

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.0455

Gnomad FIN

AF:

0.0633

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0410

Gnomad OTH

AF:

0.0478

GnomAD4 exome

AF:

0.0355

AC:

4472

AN:

126136

Hom.:

100

Cov.:

AF XY:

0.0353

AC XY:

2332

AN XY:

66132

show subpopulations

African (AFR)

AF:

0.0179

AC:

AN:

4366

American (AMR)

AF:

0.0430

AC:

223

AN:

5184

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

AN:

3206

East Asian (EAS)

AF:

0.00402

AC:

AN:

6474

South Asian (SAS)

AF:

0.0350

AC:

599

AN:

17114

European-Finnish (FIN)

AF:

0.0523

AC:

368

AN:

7040

Middle Eastern (MID)

AF:

0.0315

AC:

AN:

508

European-Non Finnish (NFE)

AF:

0.0372

AC:

2806

AN:

75442

Other (OTH)

AF:

0.0422

AC:

287

AN:

6802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

203

406

608

811

1014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.0350

AC:

5325

AN:

152262

Hom.:

131

Cov.:

AF XY:

0.0364

AC XY:

2707

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0149

AC:

619

AN:

41560

American (AMR)

AF:

0.0505

AC:

772

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

AN:

3470

East Asian (EAS)

AF:

0.00328

AC:

AN:

5178

South Asian (SAS)

AF:

0.0454

AC:

219

AN:

4826

European-Finnish (FIN)

AF:

0.0633

AC:

672

AN:

10618

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0410

AC:

2791

AN:

67998

Other (OTH)

AF:

0.0473

AC:

100

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

257

514

772

1029

1286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0207

Hom.:

Bravo

AF:

0.0329

Asia WGS

AF:

0.0240

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.7

(source)

DANN

Benign

0.66

PhyloP100

0.91

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over