rs121909799

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_000376.3(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
NM_000376.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.21

Publications

10 publications found

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 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

VDR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.0582 (below the threshold of 3.09). Trascript score misZ: 2.1887 (below the threshold of 3.09). GenCC associations: The gene is linked to vitamin D-dependent rickets, type 2A, vitamin D-dependent rickets, type 2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3 link	c.941T>G	p.Ile314Ser	missense_variant	Exon 9 of 10	ENST00000549336.6	NP_000367.1	P11473-1F1D8P8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6 link	c.941T>G	p.Ile314Ser	missense_variant	Exon 9 of 10	1	NM_000376.3	ENSP00000449573.2		P11473-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000542

AC:

AN:

184582

AF XY:

0.0000102

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000129

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1421120

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32430

American (AMR)

AF:

0.00

AC:

AN:

38558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25386

East Asian (EAS)

AF:

0.00

AC:

AN:

37372

South Asian (SAS)

AF:

0.00

AC:

AN:

80972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

9.16e-7

AC:

AN:

1091176

Other (OTH)

AF:

0.00

AC:

AN:

58928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vitamin D-dependent rickets type II with alopecia

Pathogenic:1

Dec 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

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

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.72

D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

0.43

N;N;N;.

PhyloP100

9.2

PrimateAI

Benign

0.42

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

GERP RS

5.2

Varity_R

0.75

gMVP

0.85

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over