12-47842623-ATTTTTTTTTT-ATTTTTTTTTTTT

Variant names:

• chr12-47842623-A-ATT
• rs17878969
• NM_000376.3:c.*2121_*2122dupAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000376.3(VDR):​c.*2121_*2122dupAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.075 (580 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.933
• Publications: 11 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.*2121_*2122dupAA		3_prime_UTR_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.*2121_*2122dupAA		3_prime_UTR_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2
VDR	ENST00000395324.6	c.*2121_*2122dupAA		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000378734.2
VDR	ENST00000550325.5	c.*2121_*2122dupAA		downstream_gene_variant		1		ENSP00000447173.1
VDR	ENST00000229022.9	c.*1920_*1921dupAA		downstream_gene_variant		5		ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.0755 AC: 9883 AN: 130860 Hom.: 579 Cov.: 0

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0580

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.0647

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0758

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

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

GnomAD4 genome AF: 0.0755 AC: 9877 AN: 130860 Hom.: 580 Cov.: 0 AF XY: 0.0768 AC XY: 4759 AN XY: 61944

African (AFR) AF: 0.0707 AC: 2392 AN: 33820

American (AMR) AF: 0.0579 AC: 746 AN: 12882

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 250 AN: 3284

East Asian (EAS) AF: 0.161 AC: 685 AN: 4252

South Asian (SAS) AF: 0.138 AC: 557 AN: 4042

European-Finnish (FIN) AF: 0.0744 AC: 453 AN: 6086

Middle Eastern (MID) AF: 0.0754 AC: 19 AN: 252

European-Non Finnish (NFE) AF: 0.0720 AC: 4580 AN: 63598

Other (OTH) AF: 0.0749 AC: 134 AN: 1790

Alfa AF: 0.0606 Hom.: 366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs17878969; hg19: chr12-48236406;