12-47846418-A-C

Position:

• chr12-47846418-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000549336.6(VDR):​c.941T>G​(p.Ile314Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: VDR ENST00000549336.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.21

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.941T>G	p.Ile314Ser	missense_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.941T>G	p.Ile314Ser	missense_variant	9/10	1	NM_000376.3	ENSP00000449573	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000542 AC: 1 AN: 184582 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 98038

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1421120 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 703230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.16e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1996

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 314 of the VDR protein (p.Ile314Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with vitamin D-resistant rickets (PMID: 8961271). ClinVar contains an entry for this variant (Variation ID: 7755). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VDR protein function. Experimental studies have shown that this missense change affects VDR function (PMID: 8961271). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;D;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.43	N;N;N;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.019	B;B;B;.
Vest4		0.65
MutPred		0.78		Gain of catalytic residue at P312 (P = 0.0068);Gain of catalytic residue at P312 (P = 0.0068);Gain of catalytic residue at P312 (P = 0.0068);.;
MVP		0.94
MPC		0.62
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.75
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909799; hg19: chr12-48240201;