12-47906043-T-C

Variant names:

• chr12-47906043-T-C
• rs4516035
• ENST00000622535.1:n.922T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The ENST00000622535.1(ENSG00000278385):​n.922T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 152,162 control chromosomes in the GnomAD database, including 9,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.31 (9079 hom., cov: 33)
  • Exomes 𝑓: 0.50 (2 hom.)
• Consequence: ENSG00000278385 ENST00000622535.1 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0800
• Publications: 200 publications found

Genes affected

ENSG00000278385 (HGNC:):

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.

• PP5: Variant 12-47906043-T-C is Pathogenic according to our data. Variant chr12-47906043-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3336650.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000278385	ENST00000622535.1	n.922T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
VDR	ENST00000395324.6	c.-83-23269A>G		intron_variant	Intron 1 of 9	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46411 AN: 152036 Hom.: 9077 Cov.: 33

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.375

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.500 AC: 4 AN: 8 Hom.: 2 Cov.: 0 AF XY: 0.500 AC XY: 4 AN XY: 8

African (AFR) AF: 0.00 AC: 0 AN: 2

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) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.305 AC: 46427 AN: 152154 Hom.: 9079 Cov.: 33 AF XY: 0.305 AC XY: 22689 AN XY: 74394

African (AFR) AF: 0.0855 AC: 3550 AN: 41530

American (AMR) AF: 0.308 AC: 4713 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1182 AN: 3468

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5184

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4828

European-Finnish (FIN) AF: 0.475 AC: 5028 AN: 10582

Middle Eastern (MID) AF: 0.379 AC: 110 AN: 290

European-Non Finnish (NFE) AF: 0.435 AC: 29552 AN: 67956

Other (OTH) AF: 0.315 AC: 665 AN: 2112

Alfa AF: 0.386 Hom.: 53696

Bravo AF: 0.282

Asia WGS AF: 0.159 AC: 553 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic obstructive pulmonary disease Pathogenic:1

Dr Mariam's Lab, University of the Punjab

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.65
PhyloP100		0.080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4516035; hg19: chr12-48299826;