rs121909791

Positions:

chr12-47865106-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000376.3(VDR):c.218G>A(p.Arg73Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

VDR
NM_000376.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.83

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a DNA_binding_region Nuclear receptor (size 75) in uniprot entity VDR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000376.3

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

PP5

Variant 12-47865106-C-T is Pathogenic according to our data. Variant chr12-47865106-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7746.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3 linkuse as main transcript	c.218G>A	p.Arg73Gln	missense_variant	4/10	ENST00000549336.6	NP_000367.1	P11473-1F1D8P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6 linkuse as main transcript	c.218G>A	p.Arg73Gln	missense_variant	4/10	1	NM_000376.3	ENSP00000449573.2		P11473-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251438

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461612

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vitamin D-dependent rickets type II with alopecia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 23, 1988	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2017	The R73Q variant in the VDR gene has been reported previously, in the homozygous state, in two Haitian sisters with hypocalcemic vitamin D resistant rickets, however no other genes were evaluated (Hughes et al., 1988). The R73Q variant is observed in 1/16512 (0.0061%) alleles from individuals of South Asian background, but no homozygous individuals were reported, in the ExAC dataset (Lek et al., 2016). The R73Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs in the nuclear receptor DNA biding domain at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R73Q as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 73 of the VDR protein (p.Arg73Gln). This variant is present in population databases (rs121909791, gnomAD 0.02%). This missense change has been observed in individuals with vitamin D-dependent rickets (PMID: 2849209, 28620554). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg70 to Gln. ClinVar contains an entry for this variant (Variation ID: 7746). 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 expected to disrupt VDR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects VDR function (PMID: 2849209). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;.;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

.;.;D;D;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H;H;.;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;.;D;.

Polyphen

1.0

D;D;D;.;.;.;.

Vest4

0.94

MutPred

0.84

Gain of catalytic residue at K70 (P = 0.0028);Gain of catalytic residue at K70 (P = 0.0028);Gain of catalytic residue at K70 (P = 0.0028);.;Gain of catalytic residue at K70 (P = 0.0028);Gain of catalytic residue at K70 (P = 0.0028);Gain of catalytic residue at K70 (P = 0.0028);

MVP

0.99

MPC

1.3

ClinPred

1.0

GERP RS

6.2

Varity_R

0.96

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over