rs11168293

Variant names:

• chr12-47899933-G-T
• rs11168293
• NM_000376.3:c.-84+5022C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-47899933-G-T
• chr12-47899933-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001017535.2(VDR):​c.-180C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.32 in 984,234 control chromosomes in the GnomAD database, including 52,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6256 hom., cov: 32)
  • Exomes 𝑓: 0.33 (46243 hom.)
• Consequence: VDR NM_001017535.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.175
• Publications: 22 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: G2P, Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000205537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 12-47899933-G-T is Benign according to our data. Variant chr12-47899933-G-T is described in ClinVar as Benign. ClinVar VariationId is 308891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017535.2. 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.-84+5022C>A		intron	N/A	NP_000367.1	P11473-1
	VDR	NM_001017535.2		c.-180C>A		5_prime_UTR	Exon 2 of 11	NP_001017535.1	P11473-1
	VDR	NM_001374661.1		c.-99C>A		5_prime_UTR	Exon 2 of 10	NP_001361590.1	P11473-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.-84+5022C>A		intron	N/A	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.67+4631C>A		intron	N/A	ENSP00000447173.1	P11473-2
	VDR	ENST00000546653.5	TSL:5	c.-99C>A		5_prime_UTR	Exon 2 of 7	ENSP00000448659.1	F8VRJ4

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40908 AN: 152046 Hom.: 6246 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.329 AC: 274022 AN: 832070 Hom.: 46243 Cov.: 30 AF XY: 0.330 AC XY: 126976 AN XY: 384318

African (AFR) AF: 0.139 AC: 2198 AN: 15758

American (AMR) AF: 0.264 AC: 259 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1536 AN: 5146

East Asian (EAS) AF: 0.0346 AC: 130 AN: 3762

South Asian (SAS) AF: 0.187 AC: 3072 AN: 16446

European-Finnish (FIN) AF: 0.400 AC: 112 AN: 280

Middle Eastern (MID) AF: 0.301 AC: 487 AN: 1616

European-Non Finnish (NFE) AF: 0.340 AC: 258514 AN: 760824

Other (OTH) AF: 0.283 AC: 7714 AN: 27256

GnomAD4 genome AF: 0.269 AC: 40949 AN: 152164 Hom.: 6256 Cov.: 32 AF XY: 0.269 AC XY: 20038 AN XY: 74376

African (AFR) AF: 0.152 AC: 6315 AN: 41526

American (AMR) AF: 0.260 AC: 3981 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 1000 AN: 3470

East Asian (EAS) AF: 0.0206 AC: 107 AN: 5184

South Asian (SAS) AF: 0.184 AC: 888 AN: 4828

European-Finnish (FIN) AF: 0.403 AC: 4262 AN: 10576

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23431 AN: 67972

Other (OTH) AF: 0.268 AC: 566 AN: 2112

Alfa AF: 0.308 Hom.: 11888

Bravo AF: 0.253

Asia WGS AF: 0.143 AC: 496 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs11168293; hg19: chr12-48293716; COSMIC: COSV57470224;