12-47842623-ATTTTTTTTTT-ATTTTT

Variant names:

• chr12-47842623-ATTTTT-A
• rs17878969
• ENST00000550325.5:c.*2118_*2122delAAAAA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000550325.5(VDR):​c.*2118_*2122delAAAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (14 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: VDR ENST00000550325.5 splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.759

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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00871 (1142/131054) while in subpopulation SAS AF= 0.0365 (148/4054). AF 95% confidence interval is 0.0317. There are 14 homozygotes in gnomad4. There are 567 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.*2118_*2122delAAAAA		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.*2118_*2122delAAAAA		3_prime_UTR_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1135 AN: 131054 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00562

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.00131

Gnomad MID AF: 0.0108

Gnomad NFE AF: 0.00734

Gnomad OTH AF: 0.0269

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

GnomAD4 genome AF: 0.00871 AC: 1142 AN: 131054 Hom.: 14 Cov.: 0 AF XY: 0.00914 AC XY: 567 AN XY: 62040

Gnomad4 AFR AF: 0.00387

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00564

Gnomad4 SAS AF: 0.0365

Gnomad4 FIN AF: 0.00131

Gnomad4 NFE AF: 0.00734

Gnomad4 OTH AF: 0.0296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Vitamin D-dependent rickets Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;