chr12-47846743-C-T

Position:

• chr12-47846743-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000376.3(VDR):​c.821G>A​(p.Arg274His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.81

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 12-47846743-C-T is Pathogenic according to our data. Variant chr12-47846743-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 915348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.821G>A	p.Arg274His	missense_variant	8/10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.821G>A	p.Arg274His	missense_variant	8/10	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2023	This missense change has been observed in individual(s) with clinical features of autosomal recessive vitamin D-dependent rickets (PMID: 22145479, 28620554, 35738466). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 274 of the VDR protein (p.Arg274His). ClinVar contains an entry for this variant (Variation ID: 915348). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg274 amino acid residue in VDR. Other variant(s) that disrupt this residue have been observed in individuals with VDR-related conditions (PMID: 8392085), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects VDR function (PMID: 22145479). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

Vitamin D-dependent rickets type II with alopecia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	Mar 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Dr.Nikuei Genetic Center	Jul 10, 2024	- -

Rickets Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM3strong,PM2,PP3,PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Benign	0.067	T;T;T;T
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.99	D;D;D;.
Vest4		0.95
MutPred		0.75		Gain of catalytic residue at L273 (P = 0);Gain of catalytic residue at L273 (P = 0);Gain of catalytic residue at L273 (P = 0);.;
MVP		0.99
MPC		1.4
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.93
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909796; hg19: chr12-48240526;