chr12-47843520-A-G

Variant names:

• chr12-47843520-A-G
• rs11574129
• NM_000376.3:c.*1226T>C

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.*1226T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 152,290 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (86 hom., cov: 31)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.755
• Publications: 23 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-47843520-A-G is Benign according to our data. Variant chr12-47843520-A-G is described in ClinVar as Benign. ClinVar VariationId is 308851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	NM_000376.3	MANE Select	c.*1226T>C		3_prime_UTR	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.*1025T>C		3_prime_UTR	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.*1226T>C		3_prime_UTR	Exon 10 of 10	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.*1226T>C		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.*1226T>C		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.*1025T>C		3_prime_UTR	Exon 8 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2628 AN: 151878 Hom.: 86 Cov.: 31

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.00997

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0136 AC: 4 AN: 294 Hom.: 0 Cov.: 0 AF XY: 0.0165 AC XY: 3 AN XY: 182

African (AFR) AF: 0.00 AC: 0 AN: 8

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00735 AC: 1 AN: 136

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.100 AC: 1 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0154 AC: 2 AN: 130

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0173 AC: 2626 AN: 151996 Hom.: 86 Cov.: 31 AF XY: 0.0198 AC XY: 1468 AN XY: 74306

African (AFR) AF: 0.00236 AC: 98 AN: 41474

American (AMR) AF: 0.0228 AC: 348 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.154 AC: 795 AN: 5172

South Asian (SAS) AF: 0.00998 AC: 48 AN: 4812

European-Finnish (FIN) AF: 0.0412 AC: 435 AN: 10564

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 842 AN: 67926

Other (OTH) AF: 0.0133 AC: 28 AN: 2106

Alfa AF: 0.0141 Hom.: 101

Bravo AF: 0.0172

Asia WGS AF: 0.0570 AC: 199 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.94
CADD	Benign	0.45
DANN	Benign	0.34
PhyloP100		-0.76
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: rs11574129; hg19: chr12-48237303;