12-47846450-G-A

Position:

• chr12-47846450-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000376.3(VDR):​c.909C>T​(p.Ala303=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,563,288 control chromosomes in the GnomAD database, including 11 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: VDR NM_000376.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.000006930
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.46

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-47846450-G-A is Benign according to our data. Variant chr12-47846450-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 308880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.909C>T	p.Ala303=	splice_region_variant, synonymous_variant	9/10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.909C>T	p.Ala303=	splice_region_variant, synonymous_variant	9/10	1	NM_000376.3	ENSP00000449573	P1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00204 AC: 350 AN: 171526 Hom.: 2 AF XY: 0.00223 AC XY: 202 AN XY: 90722

Gnomad AFR exome AF: 0.000688

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00168

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00331 AC: 4677 AN: 1411000 Hom.: 10 Cov.: 32 AF XY: 0.00329 AC XY: 2292 AN XY: 697186

Gnomad4 AFR exome AF: 0.000497

Gnomad4 AMR exome AF: 0.000597

Gnomad4 ASJ exome AF: 0.00174

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00188

Gnomad4 NFE exome AF: 0.00385

Gnomad4 OTH exome AF: 0.00299

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74468

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00318

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00330 Hom.: 0

Bravo AF: 0.00171

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	VDR: BP4, BP7 -

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

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.065
DANN	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000069
dbscSNV1_RF	Benign	0.0020
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: rs12721365; hg19: chr12-48240233;