12-47844974-A-C

Variant names:

• chr12-47844974-A-C
• rs731236
• NM_000376.3:c.1056T>G
• VDR p.Ile352Met

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025): 2P and 0B. O3_Moderate

The NM_000376.3(VDR):c.1056T>G (p.Ile352Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene VDR is a tumor suppressor gene (CancerMine: 6 TSG, 8 oncogene citations). The gene VDR is a known oncogene (CancerMine: 6 TSG, 8 oncogene citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I352= (synonymous): Benign (ClinVar VariationId 308877, 2 stars)

• 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, PanelApp Australia
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Our verdict: Uncertain_significance. The variant received 2 points.

• O3: Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.1056T>G	p.Ile352Met	missense	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.1056T>G	p.Ile352Met	missense	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.1206T>G	p.Ile402Met	missense	Exon 10 of 10	NP_001017536.1	P11473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.1056T>G	p.Ile352Met	missense	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.1206T>G	p.Ile402Met	missense	Exon 10 of 10	ENSP00000447173.1	P11473-2
	VDR	ENST00000229022.9	TSL:5	c.1056T>G	p.Ile352Met	missense	Exon 8 of 8	ENSP00000229022.5	A0A5K1VW50

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 71

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.049	N
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-2.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs731236;

hg19: chr12-48238757;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar