12-47842623-ATTTTTTTTTT-ATTTTTTTTTTTTTTTTTT

Variant names:

• chr12-47842623-A-ATTTTTTTT
• rs17878969
• NM_000376.3:c.*2115_*2122dupAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000376.3(VDR):​c.*2115_*2122dupAAAAAAAA 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 0.00034 (0 hom., cov: 0)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.933
• 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000376.3. 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.*2115_*2122dupAAAAAAAA		3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.*1914_*1921dupAAAAAAAA		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*2115_*2122dupAAAAAAAA		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	ENST00000549336.6	TSL:1 MANE Select	c.*2115_*2122dupAAAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000891950.1		c.*2115_*2122dupAAAAAAAA		splice_region	Exon 7 of 7	ENSP00000562009.1
	VDR	ENST00000395324.6	TSL:5	c.*2115_*2122dupAAAAAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes AF: 0.000343 AC: 45 AN: 131050 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000237

Gnomad AMI AF: 0.00117

Gnomad AMR AF: 0.000155

Gnomad ASJ AF: 0.000608

Gnomad EAS AF: 0.000468

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.000327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000424

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.000343 AC: 45 AN: 131050 Hom.: 0 Cov.: 0 AF XY: 0.000290 AC XY: 18 AN XY: 62012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000237 AC: 8 AN: 33820

American (AMR) AF: 0.000155 AC: 2 AN: 12898

Ashkenazi Jewish (ASJ) AF: 0.000608 AC: 2 AN: 3292

East Asian (EAS) AF: 0.000468 AC: 2 AN: 4270

South Asian (SAS) AF: 0.000245 AC: 1 AN: 4080

European-Finnish (FIN) AF: 0.000327 AC: 2 AN: 6124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000424 AC: 27 AN: 63654

Other (OTH) AF: 0.00 AC: 0 AN: 1782

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000277556), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93

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;