ENST00000550325.5:c.*2116_*2122delAAAAAAA

Variant names:

• chr12-47842623-ATTTTTTT-A
• rs17878969
• ENST00000550325.5:c.*2116_*2122delAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The ENST00000550325.5(VDR):​c.*2116_*2122delAAAAAAA variant causes a splice region 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 0.00067 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: VDR ENST00000550325.5 splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.759
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000672 (88/131038) while in subpopulation NFE AF = 0.000723 (46/63640). AF 95% confidence interval is 0.000556. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000550325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.*2116_*2122delAAAAAAA		3_prime_UTR	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.*1915_*1921delAAAAAAA		3_prime_UTR	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.*2116_*2122delAAAAAAA		3_prime_UTR	Exon 10 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000550325.5	TSL:1	c.*2116_*2122delAAAAAAA		splice_region	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.*2116_*2122delAAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.*2116_*2122delAAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1

Frequencies

GnomAD3 genomes AF: 0.000656 AC: 86 AN: 131038 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000465

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.000234

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000723

Gnomad OTH AF: 0.000562

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

GnomAD4 genome AF: 0.000672 AC: 88 AN: 131038 Hom.: 0 Cov.: 0 AF XY: 0.000742 AC XY: 46 AN XY: 62024

African (AFR) AF: 0.000295 AC: 10 AN: 33876

American (AMR) AF: 0.000465 AC: 6 AN: 12902

Ashkenazi Jewish (ASJ) AF: 0.000304 AC: 1 AN: 3290

East Asian (EAS) AF: 0.000235 AC: 1 AN: 4258

South Asian (SAS) AF: 0.000247 AC: 1 AN: 4054

European-Finnish (FIN) AF: 0.00343 AC: 21 AN: 6122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.000723 AC: 46 AN: 63640

Other (OTH) AF: 0.00112 AC: 2 AN: 1790

Alfa AF: 0.00 Hom.: 366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76

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;