12-47845117-C-G

Variant names:

• chr12-47845117-C-G
• rs11574113
• NM_000376.3:c.1025-112G>C

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.1025-112G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 1,529,098 control chromosomes in the GnomAD database, including 9,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1035 hom., cov: 29)
  • Exomes 𝑓: 0.11 (8516 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.512
• Publications: 18 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=-0.86).
• BP6: Variant 12-47845117-C-G is Benign according to our data. Variant chr12-47845117-C-G is described in ClinVar as Benign. ClinVar VariationId is 1182749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.1025-112G>C		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.1025-112G>C		intron_variant	Intron 9 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16742 AN: 151372 Hom.: 1036 Cov.: 29

Gnomad AFR AF: 0.0786

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.0771

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.106 AC: 145414 AN: 1377606 Hom.: 8516 AF XY: 0.105 AC XY: 72331 AN XY: 688300

African (AFR) AF: 0.0808 AC: 2594 AN: 32106

American (AMR) AF: 0.172 AC: 7444 AN: 43348

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3111 AN: 24968

East Asian (EAS) AF: 0.215 AC: 8452 AN: 39256

South Asian (SAS) AF: 0.0818 AC: 6794 AN: 83102

European-Finnish (FIN) AF: 0.188 AC: 7206 AN: 38384

Middle Eastern (MID) AF: 0.138 AC: 555 AN: 4012

European-Non Finnish (NFE) AF: 0.0971 AC: 102425 AN: 1054642

Other (OTH) AF: 0.118 AC: 6833 AN: 57788

GnomAD4 genome AF: 0.111 AC: 16743 AN: 151492 Hom.: 1035 Cov.: 29 AF XY: 0.115 AC XY: 8531 AN XY: 73978

African (AFR) AF: 0.0785 AC: 3242 AN: 41296

American (AMR) AF: 0.148 AC: 2258 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 434 AN: 3468

East Asian (EAS) AF: 0.215 AC: 1081 AN: 5028

South Asian (SAS) AF: 0.0767 AC: 368 AN: 4798

European-Finnish (FIN) AF: 0.191 AC: 2002 AN: 10486

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6830 AN: 67876

Other (OTH) AF: 0.109 AC: 230 AN: 2104

Alfa AF: 0.0534 Hom.: 54

Bravo AF: 0.110

Asia WGS AF: 0.154 AC: 536 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-0.51
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: rs11574113; hg19: chr12-48238900; COSMIC: COSV57467325;