rs10783218

Positions:

• chr12-47878960-G-A

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.146+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,614,062 control chromosomes in the GnomAD database, including 2,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (751 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1743 hom.)
• Consequence: VDR NM_000376.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001908
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.85

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=-0.77).
• BP6: Variant 12-47878960-G-A is Benign according to our data. Variant chr12-47878960-G-A is described in ClinVar as [Benign]. Clinvar id is 308886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.146+8C>T		splice_region_variant, intron_variant		ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.146+8C>T		splice_region_variant, intron_variant		1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11316 AN: 152090 Hom.: 746 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.0487

Gnomad SAS AF: 0.0450

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0359

Gnomad OTH AF: 0.0703

GnomAD3 exomes AF: 0.0450 AC: 11311 AN: 251350 Hom.: 469 AF XY: 0.0431 AC XY: 5853 AN XY: 135862

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0220

Gnomad EAS exome AF: 0.0486

Gnomad SAS exome AF: 0.0501

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0422 AC: 61654 AN: 1461854 Hom.: 1743 Cov.: 30 AF XY: 0.0421 AC XY: 30605 AN XY: 727232

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.0225

Gnomad4 EAS exome AF: 0.0550

Gnomad4 SAS exome AF: 0.0494

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0383

Gnomad4 OTH exome AF: 0.0479

GnomAD4 genome AF: 0.0745 AC: 11339 AN: 152208 Hom.: 751 Cov.: 32 AF XY: 0.0720 AC XY: 5356 AN XY: 74436

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.0367

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.0486

Gnomad4 SAS AF: 0.0452

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0359

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0495 Hom.: 264

Bravo AF: 0.0801

Asia WGS AF: 0.0590 AC: 204 AN: 3478

EpiCase AF: 0.0384

EpiControl AF: 0.0386

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.97
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
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: rs10783218; hg19: chr12-48272743;