ENST00000550325.5:c.*2117_*2122delAAAAAA

Variant names:

• chr12-47842623-ATTTTTT-A
• rs17878969
• ENST00000550325.5:c.*2117_*2122delAAAAAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000550325.5(VDR):​c.*2117_*2122delAAAAAA variant causes a splice region change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (7283 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: VDR ENST00000550325.5 splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: G2P, Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-47842623-ATTTTTT-A is Benign according to our data. Variant chr12-47842623-ATTTTTT-A is described in ClinVar as Benign. ClinVar VariationId is 308832.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.39 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.*2117_*2122delAAAAAA		3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.*1916_*1921delAAAAAA		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*2117_*2122delAAAAAA		3_prime_UTR	Exon 10 of 10	NP_001017536.1	P11473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000550325.5	TSL:1	c.*2117_*2122delAAAAAA		splice_region	Exon 10 of 10	ENSP00000447173.1	P11473-2
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.*2117_*2122delAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.*2117_*2122delAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1	P11473-2

Frequencies

GnomAD3 genomes AF: 0.339 AC: 44435 AN: 131096 Hom.: 7284 Cov.: 0

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.336

Gnomad EAS AF: 0.0666

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.340

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

GnomAD4 genome AF: 0.339 AC: 44437 AN: 131098 Hom.: 7283 Cov.: 0 AF XY: 0.338 AC XY: 20999 AN XY: 62068

African (AFR) AF: 0.272 AC: 9236 AN: 33900

American (AMR) AF: 0.308 AC: 3977 AN: 12904

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 1107 AN: 3296

East Asian (EAS) AF: 0.0668 AC: 284 AN: 4252

South Asian (SAS) AF: 0.325 AC: 1317 AN: 4054

European-Finnish (FIN) AF: 0.404 AC: 2481 AN: 6138

Middle Eastern (MID) AF: 0.335 AC: 85 AN: 254

European-Non Finnish (NFE) AF: 0.394 AC: 25094 AN: 63644

Other (OTH) AF: 0.341 AC: 614 AN: 1800

Alfa AF: 0.254 Hom.: 366

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Vitamin D-dependent rickets (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17878969; hg19: chr12-48236406;