rs11574050

Variant names:

• chr12-47878678-G-A
• rs11574050
• NM_000376.3:c.146+290C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47878678-G-A
• chr12-47878678-G-C
• chr12-47878678-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364085.2(VDR):​c.146+290C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0597 in 493,084 control chromosomes in the GnomAD database, including 1,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (395 hom., cov: 32)
  • Exomes 𝑓: 0.056 (638 hom.)
• Consequence: VDR NM_001364085.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.738
• Publications: 7 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=-0.89).
• BP6: Variant 12-47878678-G-A is Benign according to our data. Variant chr12-47878678-G-A is described in ClinVar as Benign. ClinVar VariationId is 1231146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364085.2. 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.146+290C>T		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.146+290C>T		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.296+290C>T		intron	N/A	NP_001017536.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.146+290C>T		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.296+290C>T		intron	N/A	ENSP00000447173.1
	VDR	ENST00000229022.9	TSL:5	c.146+290C>T		intron	N/A	ENSP00000229022.5

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 10178 AN: 152110 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0930

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0699

GnomAD4 exome AF: 0.0565 AC: 19248 AN: 340856 Hom.: 638 AF XY: 0.0549 AC XY: 10317 AN XY: 187996

African (AFR) AF: 0.0931 AC: 924 AN: 9930

American (AMR) AF: 0.0711 AC: 1796 AN: 25258

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 341 AN: 11712

East Asian (EAS) AF: 0.128 AC: 1899 AN: 14790

South Asian (SAS) AF: 0.0461 AC: 2561 AN: 55582

European-Finnish (FIN) AF: 0.0680 AC: 1050 AN: 15440

Middle Eastern (MID) AF: 0.0390 AC: 55 AN: 1410

European-Non Finnish (NFE) AF: 0.0506 AC: 9565 AN: 189022

Other (OTH) AF: 0.0597 AC: 1057 AN: 17712

GnomAD4 genome AF: 0.0670 AC: 10194 AN: 152228 Hom.: 395 Cov.: 32 AF XY: 0.0672 AC XY: 5002 AN XY: 74422

African (AFR) AF: 0.0930 AC: 3861 AN: 41514

American (AMR) AF: 0.0664 AC: 1016 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3468

East Asian (EAS) AF: 0.124 AC: 645 AN: 5182

South Asian (SAS) AF: 0.0513 AC: 248 AN: 4830

European-Finnish (FIN) AF: 0.0618 AC: 655 AN: 10602

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0516 AC: 3510 AN: 68018

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0491 Hom.: 132

Bravo AF: 0.0704

Asia WGS AF: 0.101 AC: 354 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.77
PhyloP100		-0.74
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11574050; hg19: chr12-48272461;