rs11574129

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.*1226T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.*1226T>C		3_prime_UTR_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2
VDR	ENST00000550325.5	c.*1226T>C		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000447173.1
VDR	ENST00000229022.9	c.*1025T>C		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000229022.5
VDR	ENST00000395324.6	c.*1226T>C		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000378734.2

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.94
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;