12-47844859-G-T

Variant names:

• chr12-47844859-G-T
• rs121909800
• NM_000376.3:c.1171C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_000376.3(VDR):​c.1171C>A​(p.Arg391Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R391H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.69
• Publications: 15 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-47844858-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2137319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 12-47844859-G-T is Pathogenic according to our data. Variant chr12-47844859-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 264696.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.1171C>A	p.Arg391Ser	missense	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.1171C>A	p.Arg391Ser	missense	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.1321C>A	p.Arg441Ser	missense	Exon 10 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.1171C>A	p.Arg391Ser	missense	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.1321C>A	p.Arg441Ser	missense	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.1171C>A	p.Arg391Ser	missense	Exon 8 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

May 03, 2016

American University of Beirut, Same Uiversity Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		3.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.87		Gain of disorder (P = 0.0665)
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909800; hg19: chr12-48238642;