chr12-47842767-G-C

Position:

• chr12-47842767-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000376.3(VDR):​c.*1979C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 152,166 control chromosomes in the GnomAD database, including 69,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (69047 hom., cov: 29)
  • Exomes 𝑓: 0.96 (21 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.12

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-47842767-G-C is Benign according to our data. Variant chr12-47842767-G-C is described in ClinVar as [Benign]. Clinvar id is 308840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VDR	NM_000376.3	c.*1979C>G		3_prime_UTR_variant	10/10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336	c.*1979C>G		3_prime_UTR_variant	10/10	1	NM_000376.3	ENSP00000449573.2
VDR	ENST00000550325	c.*1979C>G		3_prime_UTR_variant	10/10	1		ENSP00000447173.1
VDR	ENST00000229022	c.*1778C>G		3_prime_UTR_variant	8/8	5		ENSP00000229022.5
VDR	ENST00000395324	c.*1979C>G		3_prime_UTR_variant	10/10	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.952 AC: 144765 AN: 152002 Hom.: 68988 Cov.: 29

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.929

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.930

Gnomad OTH AF: 0.943

GnomAD4 exome AF: 0.957 AC: 44 AN: 46 Hom.: 21 Cov.: 0 AF XY: 0.941 AC XY: 32 AN XY: 34

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.938

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.952 AC: 144883 AN: 152120 Hom.: 69047 Cov.: 29 AF XY: 0.953 AC XY: 70838 AN XY: 74350

Gnomad4 AFR AF: 0.989

Gnomad4 AMR AF: 0.956

Gnomad4 ASJ AF: 0.920

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.988

Gnomad4 FIN AF: 0.929

Gnomad4 NFE AF: 0.930

Gnomad4 OTH AF: 0.944

Alfa AF: 0.930 Hom.: 3070

Bravo AF: 0.955

Asia WGS AF: 0.993 AC: 3455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Vitamin D-dependent rickets type II with alopecia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.47
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs2544043; hg19: chr12-48236550;