rs267607169

Variant names:

• chr12-47844994-C-A
• rs267607169
• NM_000376.3:c.1036G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47844994-C-A
• chr12-47844994-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000376.3(VDR):​c.1036G>T​(p.Val346Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,492 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V346M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VDR NM_000376.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 0 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-47844994-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 7759.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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.1036G>T	p.Val346Leu	missense	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.1036G>T	p.Val346Leu	missense	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.1186G>T	p.Val396Leu	missense	Exon 10 of 10	NP_001017536.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.1036G>T	p.Val346Leu	missense	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.1186G>T	p.Val396Leu	missense	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.1036G>T	p.Val346Leu	missense	Exon 8 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460492 Hom.: 0 Cov.: 53 AF XY: 0.00000138 AC XY: 1 AN XY: 726632

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111906

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.66	N
PhyloP100		7.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.026	D
Polyphen		0.73	P
Vest4		0.56
MutPred		0.58		Gain of catalytic residue at P341 (P = 0.0047)
MVP		0.86
MPC		0.42
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.78
gMVP		0.80
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267607169; hg19: chr12-48238777;