12-47844309-G-C

Variant names:

• chr12-47844309-G-C
• rs11574119
• NM_000376.3:c.*437C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.906
• Publications: 7 publications found

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

ACMG classification

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5326 AN: 152144 Hom.: 130 Cov.: 32

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.: 0 AF XY: 0.0353 AC XY: 2332 AN XY: 66132

African (AFR) AF: 0.0179 AC: 78 AN: 4366

American (AMR) AF: 0.0430 AC: 223 AN: 5184

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 69 AN: 3206

East Asian (EAS) AF: 0.00402 AC: 26 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: 16 AN: 508

European-Non Finnish (NFE) AF: 0.0372 AC: 2806 AN: 75442

Other (OTH) AF: 0.0422 AC: 287 AN: 6802

GnomAD4 genome AF: 0.0350 AC: 5325 AN: 152262 Hom.: 131 Cov.: 32 AF XY: 0.0364 AC XY: 2707 AN XY: 74438

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: 81 AN: 3470

East Asian (EAS) AF: 0.00328 AC: 17 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: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2791 AN: 67998

Other (OTH) AF: 0.0473 AC: 100 AN: 2114

Alfa AF: 0.0207 Hom.: 7

Bravo AF: 0.0329

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely 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: 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.7
DANN	Benign	0.66
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11574119; hg19: chr12-48238092;