12-47842840-G-T

Variant names:

• chr12-47842840-G-T
• rs9729
• NM_000376.3:c.*1906C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000376.3(VDR):​c.*1906C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 151,768 control chromosomes in the GnomAD database, including 21,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21593 hom., cov: 30)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0720
• Publications: 41 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=-0.92).
• BP6: Variant 12-47842840-G-T is Benign according to our data. Variant chr12-47842840-G-T is described in ClinVar as Benign. ClinVar VariationId is 308841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

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.*1906C>A		3_prime_UTR	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.*1705C>A		3_prime_UTR	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.*1906C>A		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.*1906C>A		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.*1906C>A		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.*1705C>A		3_prime_UTR	Exon 8 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80395 AN: 151654 Hom.: 21572 Cov.: 30

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.539

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.525

Gnomad OTH AF: 0.538

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.530 AC: 80466 AN: 151766 Hom.: 21593 Cov.: 30 AF XY: 0.530 AC XY: 39314 AN XY: 74164

African (AFR) AF: 0.568 AC: 23492 AN: 41358

American (AMR) AF: 0.499 AC: 7615 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2016 AN: 3466

East Asian (EAS) AF: 0.291 AC: 1500 AN: 5158

South Asian (SAS) AF: 0.539 AC: 2590 AN: 4806

European-Finnish (FIN) AF: 0.550 AC: 5772 AN: 10502

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.525 AC: 35657 AN: 67922

Other (OTH) AF: 0.540 AC: 1136 AN: 2102

Alfa AF: 0.523 Hom.: 34845

Bravo AF: 0.531

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.50
PhyloP100		0.072
Mutation Taster		=100/0	polymorphism (auto)

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: rs9729; hg19: chr12-48236623;