12-47844438-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000376.3(VDR):c.*308C>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 0.52 in 539,752 control chromosomes in the GnomAD database, including 74,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21596 hom., cov: 33)
  • Exomes 𝑓: 0.52 (52968 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.58

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-47844438-G-T is Benign according to our data. Variant chr12-47844438-G-T is described in ClinVar as [Benign]. Clinvar id is 308868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.*308C>A		3_prime_UTR_variant	10/10	ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.*308C>A		3_prime_UTR_variant	10/10	1	NM_000376.3	P1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80505 AN: 151978 Hom.: 21577 Cov.: 33

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.538

GnomAD4 exome AF: 0.517 AC: 200273 AN: 387656 Hom.: 52968 Cov.: 2 AF XY: 0.519 AC XY: 105533 AN XY: 203216

Gnomad4 AFR exome AF: 0.570

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.561

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.555

Gnomad4 FIN exome AF: 0.553

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.527

GnomAD4 genome AF: 0.530 AC: 80575 AN: 152096 Hom.: 21596 Cov.: 33 AF XY: 0.530 AC XY: 39386 AN XY: 74334

Gnomad4 AFR AF: 0.563

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.583

Gnomad4 EAS AF: 0.292

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.527

Gnomad4 OTH AF: 0.540

Alfa AF: 0.487 Hom.: 3564

Bravo AF: 0.524

Asia WGS AF: 0.463 AC: 1610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2018

This variant is associated with the following publications: (PMID: 29241179) -

Vitamin D-dependent rickets type II with alopecia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, no assertion criteria provided

case-control

Genetics Laboratory, Lanzhou University

Apr 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.059
Dann	Benign	0.45

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

LitVar

Other links and lift over

dbSNP: rs739837; hg19: chr12-48238221; COSMIC: COSV57468674; COSMIC: COSV57468674;