12-47841772-T-A

Variant names:

• chr12-47841772-T-A
• rs11574139
• NM_000376.3:c.*2974A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000376.3(VDR):​c.*2974A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 152,460 control chromosomes in the GnomAD database, including 109 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 0.032 (109 hom., cov: 33)
  • Exomes 𝑓: 0.048 (0 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0700
• Publications: 10 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=-0.84).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0322 (4912/152314) while in subpopulation AMR AF = 0.046 (704/15300). AF 95% confidence interval is 0.0432. There are 109 homozygotes in GnomAd4. There are 2518 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 109 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.*2974A>T		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.*2974A>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_000376.3	ENSP00000449573.2
VDR	ENST00000395324.6	c.*2974A>T		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4913 AN: 152196 Hom.: 108 Cov.: 33

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0630

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0368

Gnomad OTH AF: 0.0406

GnomAD4 exome AF: 0.0479 AC: 7 AN: 146 Hom.: 0 Cov.: 0 AF XY: 0.0250 AC XY: 2 AN XY: 80

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0441 AC: 6 AN: 136

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.001998), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0322 AC: 4912 AN: 152314 Hom.: 109 Cov.: 33 AF XY: 0.0338 AC XY: 2518 AN XY: 74474

African (AFR) AF: 0.0141 AC: 585 AN: 41570

American (AMR) AF: 0.0460 AC: 704 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.00308 AC: 16 AN: 5190

South Asian (SAS) AF: 0.0449 AC: 217 AN: 4828

European-Finnish (FIN) AF: 0.0630 AC: 668 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0368 AC: 2505 AN: 68026

Other (OTH) AF: 0.0402 AC: 85 AN: 2116

Alfa AF: 0.0341 Hom.: 7

Bravo AF: 0.0300

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.75
PhyloP100		0.070
Mutation Taster		=100/0	polymorphism

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: rs11574139; hg19: chr12-48235555;