12-47842623-ATTTTTTTTTT-ATTTTTTTTTTTTTT

Variant names:

• chr12-47842623-A-ATTTT
• rs17878969
• NM_000376.3:c.*2119_*2122dupAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000376.3(VDR):​c.*2119_*2122dupAAAA 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 0.0058 (16 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: Labcorp Genetics (formerly Invitae), G2P
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0058 (760/131002) while in subpopulation AFR AF = 0.0198 (668/33822). AF 95% confidence interval is 0.0185. There are 16 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.*2119_*2122dupAAAA		3_prime_UTR	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.*1918_*1921dupAAAA		3_prime_UTR	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.*2119_*2122dupAAAA		3_prime_UTR	Exon 10 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.*2119_*2122dupAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000395324.6	TSL:5	c.*2119_*2122dupAAAA		3_prime_UTR	Exon 10 of 10	ENSP00000378734.2
	VDR	ENST00000550325.5	TSL:1	c.*2119_*2122dupAAAA		downstream_gene	N/A	ENSP00000447173.1

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 758 AN: 131004 Hom.: 16 Cov.: 0

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00434

Gnomad ASJ AF: 0.000304

Gnomad EAS AF: 0.000234

Gnomad SAS AF: 0.00172

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000157

Gnomad OTH AF: 0.00954

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: 0.00580 AC: 760 AN: 131002 Hom.: 16 Cov.: 0 AF XY: 0.00558 AC XY: 346 AN XY: 62014

African (AFR) AF: 0.0198 AC: 668 AN: 33822

American (AMR) AF: 0.00434 AC: 56 AN: 12900

Ashkenazi Jewish (ASJ) AF: 0.000304 AC: 1 AN: 3292

East Asian (EAS) AF: 0.000235 AC: 1 AN: 4256

South Asian (SAS) AF: 0.00173 AC: 7 AN: 4052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6124

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

European-Non Finnish (NFE) AF: 0.000157 AC: 10 AN: 63658

Other (OTH) AF: 0.00949 AC: 17 AN: 1792

Alfa AF: 0.00 Hom.: 366

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;