12-47842623-ATTTTTTTTTT-ATTTTTTTTT

Variant names:

• chr12-47842623-AT-A
• rs17878969
• NM_000376.3:c.*2122delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000376.3(VDR):​c.*2122delA 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 0.031 (116 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
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

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.*2122delA		3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.*1921delA		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*2122delA		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.*2122delA		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000891950.1		c.*2122delA		splice_region	Exon 7 of 7	ENSP00000562009.1
	VDR	ENST00000395324.6	TSL:5	c.*2122delA		3_prime_UTR	Exon 10 of 10	ENSP00000378734.2	P11473-1

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4104 AN: 130958 Hom.: 116 Cov.: 0

Gnomad AFR AF: 0.0916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.0131

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.00515

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.00696

Gnomad OTH AF: 0.0337

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0314 AC: 4111 AN: 130958 Hom.: 116 Cov.: 0 AF XY: 0.0307 AC XY: 1904 AN XY: 62002

African (AFR) AF: 0.0918 AC: 3101 AN: 33796

American (AMR) AF: 0.0221 AC: 285 AN: 12892

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 43 AN: 3292

East Asian (EAS) AF: 0.0333 AC: 142 AN: 4258

South Asian (SAS) AF: 0.00518 AC: 21 AN: 4054

European-Finnish (FIN) AF: 0.00180 AC: 11 AN: 6124

Middle Eastern (MID) AF: 0.0200 AC: 5 AN: 250

European-Non Finnish (NFE) AF: 0.00696 AC: 443 AN: 63650

Other (OTH) AF: 0.0336 AC: 60 AN: 1788

Alfa AF: 0.00390 Hom.: 366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.93
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17878969; hg19: chr12-48236406;