12-47842623-ATTTTTTTTTT-ATTTTTTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_000376.3(VDR):​c.*2121_*2122delAA 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 0.0029 (1 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.602

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00291 (381/131068) while in subpopulation AFR AF= 0.01 (340/33880). AF 95% confidence interval is 0.00916. There are 1 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 379 AN: 131068 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000314

Gnomad OTH AF: 0.00168

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00291 AC: 381 AN: 131068 Hom.: 1 Cov.: 0 AF XY: 0.00259 AC XY: 161 AN XY: 62046

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000247

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000314

Gnomad4 OTH AF: 0.00167

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs17878969; hg19: chr12-48236406;