12-47842623-ATTTTTTTTTT-ATTTTTTTTTTTTTT

Position:

• chr12-47842623-ATTTTTTTTTT-ATTTTTTTTTTTTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000376.3(VDR):​c.*2122_*2123insAAAA 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 0.0058 (16 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

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 Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0058 (760/131002) while in subpopulation AFR AF= 0.0198 (668/33822). AF 95% confidence interval is 0.0185. There are 16 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VDR	NM_000376.3	c.*2122_*2123insAAAA		3_prime_UTR_variant	10/10	ENST00000549336.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VDR	ENST00000549336.6	c.*2122_*2123insAAAA		3_prime_UTR_variant	10/10	1	NM_000376.3	P1
VDR	ENST00000395324.6	c.*2122_*2123insAAAA		3_prime_UTR_variant	10/10	5		P1
VDR	ENST00000550325.5			downstream_gene_variant		1
VDR	ENST00000229022.9			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 758 AN: 131004 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00434

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.000234

Gnomad SAS AF: 0.00172

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000157

Gnomad OTH AF: 0.00954

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

GnomAD4 genome AF: 0.00580 AC: 760 AN: 131002 Hom.: 16 Cov.: 0 AF XY: 0.00558 AC XY: 346 AN XY: 62014

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.00434

Gnomad4 ASJ AF: 0.000304

Gnomad4 EAS AF: 0.000235

Gnomad4 SAS AF: 0.00173

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000157

Gnomad4 OTH AF: 0.00949

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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;