NM_000376.3:c.1056T>G

Variant names:

• chr12-47844974-A-C
• rs731236
• NM_000376.3:c.1056T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000376.3(VDR):​c.1056T>G​(p.Ile352Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I352I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• Publications: 1 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: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41640562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.1056T>G	p.Ile352Met	missense_variant	Exon 10 of 10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.1056T>G	p.Ile352Met	missense_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	0.079
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.93	D;D;D;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.049	N
LIST_S2	Uncertain	0.94	.;.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.1	M;M;M;.
PhyloP100		-2.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.58	P;P;P;.
Vest4		0.25
MutPred		0.62		Gain of catalytic residue at A349 (P = 0.0263);Gain of catalytic residue at A349 (P = 0.0263);Gain of catalytic residue at A349 (P = 0.0263);.;
MVP		0.68
MPC		0.98
ClinPred		0.83	D
GERP RS		-7.9
Varity_R		0.63
gMVP		0.73
Mutation Taster		=76/24	polymorphism

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: rs731236; hg19: chr12-48238757;