rs7139166

Positions:

• chr12-47906551-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000622535.1(ENSG00000278385):​n.1430C>G 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 152,120 control chromosomes in the GnomAD database, including 9,076 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (9075 hom., cov: 32)
  • Exomes 𝑓: 0.30 (1 hom.)
• Consequence: ENST00000622535.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.697

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• 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.1430C>G		non_coding_transcript_exon_variant	1/1
VDR	ENST00000395324.6	c.-83-23777G>C		intron_variant		5		ENSP00000378734	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46375 AN: 151980 Hom.: 9073 Cov.: 32

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.381

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.300 AC: 6 AN: 20 Hom.: 1 Cov.: 0 AF XY: 0.357 AC XY: 5 AN XY: 14

Gnomad4 ASJ exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.305 AC: 46392 AN: 152100 Hom.: 9075 Cov.: 32 AF XY: 0.305 AC XY: 22659 AN XY: 74330

Gnomad4 AFR AF: 0.0856

Gnomad4 AMR AF: 0.309

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.0222

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.475

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.314

Alfa AF: 0.367 Hom.: 1433

Bravo AF: 0.282

Asia WGS AF: 0.158 AC: 549 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.3
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7139166; hg19: chr12-48300334;