rs4516035

Positions:

• chr12-47906043-T-C

Variant summary

Our verdict is Benign. Variant got -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: ENST00000622535.1 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0800

Genes affected

(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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000622535.1	n.922T>C		non_coding_transcript_exon_variant	1/1
VDR	ENST00000395324.6	c.-83-23269A>G		intron_variant		5		ENSP00000378734	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.00

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

Gnomad4 AFR AF: 0.0855

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.315

Alfa AF: 0.398 Hom.: 26527

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

Likely pathogenic, no assertion criteria provided

case-control

Dr Mariam's Lab, University of the Punjab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.2
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4516035; hg19: chr12-48299826;