chr12-47842767-G-C

Variant names:

• chr12-47842767-G-C
• rs2544043
• NM_000376.3:c.*1979C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.*1979C>G		3_prime_UTR	Exon 10 of 10	NP_000367.1	P11473-1
	VDR	NM_001364085.2		c.*1778C>G		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*1979C>G		3_prime_UTR	Exon 10 of 10	NP_001017536.1	P11473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.*1979C>G		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.*1979C>G		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1	P11473-2
	VDR	ENST00000229022.9	TSL:5	c.*1778C>G		3_prime_UTR	Exon 8 of 8	ENSP00000229022.5	A0A5K1VW50

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

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 1.00 AC: 4 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.938 AC: 30 AN: 32

Other (OTH) AF: 1.00 AC: 4 AN: 4

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

African (AFR) AF: 0.989 AC: 41018 AN: 41492

American (AMR) AF: 0.956 AC: 14618 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3194 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5154 AN: 5156

South Asian (SAS) AF: 0.988 AC: 4767 AN: 4824

European-Finnish (FIN) AF: 0.929 AC: 9824 AN: 10572

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.930 AC: 63245 AN: 68000

Other (OTH) AF: 0.944 AC: 1988 AN: 2106

Alfa AF: 0.930 Hom.: 3070

Bravo AF: 0.955

Asia WGS AF: 0.993 AC: 3455 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.47
DANN	Benign	0.41
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2544043; hg19: chr12-48236550;