rs10783218

Variant names:

• chr12-47878960-G-A
• rs10783218
• NM_000376.3:c.146+8C>T

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.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
• Publications: 20 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=-0.77).
• BP6: Variant 12-47878960-G-A is Benign according to our data. Variant chr12-47878960-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.146+8C>T		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.146+8C>T		splice_region_variant, intron_variant	Intron 3 of 9	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

GnomAD2 exomes AF: 0.0450 AC: 11311 AN: 251350 AF XY: 0.0431

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 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

African (AFR) AF: 0.193 AC: 6476 AN: 33476

American (AMR) AF: 0.0235 AC: 1052 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 587 AN: 26136

East Asian (EAS) AF: 0.0550 AC: 2185 AN: 39698

South Asian (SAS) AF: 0.0494 AC: 4265 AN: 86254

European-Finnish (FIN) AF: 0.0236 AC: 1260 AN: 53402

Middle Eastern (MID) AF: 0.0609 AC: 351 AN: 5768

European-Non Finnish (NFE) AF: 0.0383 AC: 42587 AN: 1112004

Other (OTH) AF: 0.0479 AC: 2891 AN: 60392

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

African (AFR) AF: 0.178 AC: 7393 AN: 41498

American (AMR) AF: 0.0367 AC: 562 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.0486 AC: 252 AN: 5180

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4822

European-Finnish (FIN) AF: 0.0192 AC: 204 AN: 10618

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0359 AC: 2443 AN: 67992

Other (OTH) AF: 0.0691 AC: 146 AN: 2114

Alfa AF: 0.0497 Hom.: 759

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.97
DANN	Benign	0.71
PhyloP100		-1.8
PromoterAI		0.0021	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10783218; hg19: chr12-48272743;