12-47844438-G-T

Variant names:

• chr12-47844438-G-T
• rs739837
• NM_000376.3:c.*308C>A

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.*308C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 539,752 control chromosomes in the GnomAD database, including 74,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21596 hom., cov: 33)
  • Exomes 𝑓: 0.52 (52968 hom.)
• Consequence: VDR NM_000376.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.58
• Publications: 119 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=-0.92).
• BP6: Variant 12-47844438-G-T is Benign according to our data. Variant chr12-47844438-G-T is described in ClinVar as Benign. ClinVar VariationId is 308868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 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.*308C>A		3_prime_UTR	Exon 10 of 10	NP_000367.1
	VDR	NM_001364085.2		c.*107C>A		3_prime_UTR	Exon 10 of 10	NP_001351014.1
	VDR	NM_001017536.2		c.*308C>A		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.*308C>A		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.*308C>A		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.*107C>A		3_prime_UTR	Exon 8 of 8	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80505 AN: 151978 Hom.: 21577 Cov.: 33

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.589

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.538

GnomAD4 exome AF: 0.517 AC: 200273 AN: 387656 Hom.: 52968 Cov.: 2 AF XY: 0.519 AC XY: 105533 AN XY: 203216

African (AFR) AF: 0.570 AC: 6382 AN: 11198

American (AMR) AF: 0.454 AC: 7355 AN: 16190

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 6702 AN: 11942

East Asian (EAS) AF: 0.305 AC: 8216 AN: 26980

South Asian (SAS) AF: 0.555 AC: 22931 AN: 41306

European-Finnish (FIN) AF: 0.553 AC: 14113 AN: 25540

Middle Eastern (MID) AF: 0.628 AC: 1062 AN: 1692

European-Non Finnish (NFE) AF: 0.528 AC: 121640 AN: 230296

Other (OTH) AF: 0.527 AC: 11872 AN: 22512

GnomAD4 genome AF: 0.530 AC: 80575 AN: 152096 Hom.: 21596 Cov.: 33 AF XY: 0.530 AC XY: 39386 AN XY: 74334

African (AFR) AF: 0.563 AC: 23370 AN: 41484

American (AMR) AF: 0.497 AC: 7605 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2021 AN: 3468

East Asian (EAS) AF: 0.292 AC: 1510 AN: 5168

South Asian (SAS) AF: 0.540 AC: 2604 AN: 4824

European-Finnish (FIN) AF: 0.552 AC: 5844 AN: 10582

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35781 AN: 67956

Other (OTH) AF: 0.540 AC: 1142 AN: 2114

Alfa AF: 0.490 Hom.: 3694

Bravo AF: 0.524

Asia WGS AF: 0.463 AC: 1610 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29241179)

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

Jan 13, 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.

Periodontitis Benign:1

Apr 20, 2023

Genetics Laboratory, Lanzhou University

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.059
DANN	Benign	0.45
PhyloP100		-1.6
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: rs739837; hg19: chr12-48238221; COSMIC: COSV57468674; COSMIC: COSV57468674;