rs2853563

Variant names:

• chr12-47841955-C-T
• rs2853563
• NM_000376.3:c.*2791G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-47841955-C-T
• chr12-47841955-C-G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000376.3(VDR):​c.*2791G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0775 in 152,352 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (761 hom., cov: 33)
  • Exomes 𝑓: 0.051 (0 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74
• Publications: 25 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-47841955-C-T is Benign according to our data. Variant chr12-47841955-C-T is described in ClinVar as Benign. ClinVar VariationId is 308816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

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.*2791G>A		3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.*2590G>A		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*2791G>A		3_prime_UTR	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.*2791G>A		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000395324.6	TSL:5	c.*2791G>A		3_prime_UTR	Exon 10 of 10	ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes AF: 0.0773 AC: 11758 AN: 152096 Hom.: 754 Cov.: 33

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0598

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0373

Gnomad OTH AF: 0.0712

GnomAD4 exome AF: 0.0507 AC: 7 AN: 138 Hom.: 0 Cov.: 0 AF XY: 0.0395 AC XY: 3 AN XY: 76

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0507 AC: 7 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000344060), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0775 AC: 11796 AN: 152214 Hom.: 761 Cov.: 33 AF XY: 0.0771 AC XY: 5738 AN XY: 74404

African (AFR) AF: 0.172 AC: 7146 AN: 41502

American (AMR) AF: 0.0597 AC: 913 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3472

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5190

South Asian (SAS) AF: 0.0477 AC: 230 AN: 4824

European-Finnish (FIN) AF: 0.0629 AC: 665 AN: 10578

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0373 AC: 2535 AN: 68028

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0630 Hom.: 107

Bravo AF: 0.0813

Asia WGS AF: 0.0430 AC: 150 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.14
DANN	Benign	0.64
PhyloP100		-1.7
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: rs2853563; hg19: chr12-48235738;