rs739837

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr12-47844438-G-T
• chr12-47844438-G-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.*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: 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=-0.92).
• 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

Sel.	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	P11473-1
	VDR	NM_001364085.2		c.*107C>A		3_prime_UTR	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
	VDR	NM_001017536.2		c.*308C>A		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.*308C>A		3_prime_UTR	Exon 10 of 10	ENSP00000449573.2	P11473-1
	VDR	ENST00000550325.5	TSL:1	c.*308C>A		3_prime_UTR	Exon 10 of 10	ENSP00000447173.1	P11473-2
	VDR	ENST00000229022.9	TSL:5	c.*107C>A		3_prime_UTR	Exon 8 of 8	ENSP00000229022.5	A0A5K1VW50

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Periodontitis (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	-0.92
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;