12-47846052-C-T

Variant names:

• chr12-47846052-C-T
• rs1544410
• NM_000376.3:c.1024+283G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000376.3(VDR):​c.1024+283G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,108 control chromosomes in the GnomAD database, including 9,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (9698 hom., cov: 32)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, single submitter P:1 B:2
• Conservation: PhyloP100: -0.0330
• Publications: 1136 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-47846052-C-T is Benign according to our data. Variant chr12-47846052-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259287.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.1024+283G>A		intron_variant	Intron 9 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.1024+283G>A		intron_variant	Intron 9 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52971 AN: 151990 Hom.: 9691 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.0636

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.367

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.348 AC: 53009 AN: 152108 Hom.: 9698 Cov.: 32 AF XY: 0.346 AC XY: 25737 AN XY: 74350

African (AFR) AF: 0.303 AC: 12552 AN: 41480

American (AMR) AF: 0.306 AC: 4678 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1256 AN: 3468

East Asian (EAS) AF: 0.0639 AC: 331 AN: 5178

South Asian (SAS) AF: 0.446 AC: 2150 AN: 4826

European-Finnish (FIN) AF: 0.332 AC: 3513 AN: 10566

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.403 AC: 27385 AN: 67990

Other (OTH) AF: 0.371 AC: 784 AN: 2116

Alfa AF: 0.381 Hom.: 41027

Bravo AF: 0.338

Asia WGS AF: 0.279 AC: 969 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1

Jul 14, 2022

Bioengineering and Technology, Gauhati University

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not provided Benign:1

Mar 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.8
DANN	Benign	0.54
PhyloP100		-0.033
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: rs1544410; hg19: chr12-48239835;