NM_000376.3:c.-84+5133G>C

Variant names:

• chr12-47899822-C-G
• rs11168292
• NM_000376.3:c.-84+5133G>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.-84+5133G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 875,608 control chromosomes in the GnomAD database, including 43,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6249 hom., cov: 33)
  • Exomes 𝑓: 0.32 (37357 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.420
• Publications: 20 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

ENSG00000205537 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-47899822-C-G is Benign according to our data. Variant chr12-47899822-C-G is described in ClinVar as Benign. ClinVar VariationId is 308889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.341 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.-84+5133G>C		intron	N/A	NP_000367.1
	VDR	NM_001364085.2		c.-84+5133G>C		intron	N/A	NP_001351014.1
	VDR	NM_001017536.2		c.67+4742G>C		intron	N/A	NP_001017536.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VDR	ENST00000549336.6	TSL:1 MANE Select	c.-84+5133G>C		intron	N/A	ENSP00000449573.2
	VDR	ENST00000550325.5	TSL:1	c.67+4742G>C		intron	N/A	ENSP00000447173.1
	VDR	ENST00000395324.6	TSL:5	c.-83-17048G>C		intron	N/A	ENSP00000378734.2

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40829 AN: 152036 Hom.: 6241 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.317 AC: 229214 AN: 723454 Hom.: 37357 Cov.: 9 AF XY: 0.318 AC XY: 107058 AN XY: 336550

African (AFR) AF: 0.131 AC: 1797 AN: 13746

American (AMR) AF: 0.252 AC: 215 AN: 854

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1310 AN: 4504

East Asian (EAS) AF: 0.0233 AC: 76 AN: 3262

South Asian (SAS) AF: 0.172 AC: 2489 AN: 14476

European-Finnish (FIN) AF: 0.366 AC: 85 AN: 232

Middle Eastern (MID) AF: 0.293 AC: 424 AN: 1446

European-Non Finnish (NFE) AF: 0.327 AC: 216368 AN: 661110

Other (OTH) AF: 0.271 AC: 6450 AN: 23824

GnomAD4 genome AF: 0.269 AC: 40866 AN: 152154 Hom.: 6249 Cov.: 33 AF XY: 0.269 AC XY: 19984 AN XY: 74374

African (AFR) AF: 0.152 AC: 6300 AN: 41528

American (AMR) AF: 0.260 AC: 3974 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3470

East Asian (EAS) AF: 0.0206 AC: 107 AN: 5188

South Asian (SAS) AF: 0.177 AC: 854 AN: 4828

European-Finnish (FIN) AF: 0.403 AC: 4263 AN: 10568

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23407 AN: 67972

Other (OTH) AF: 0.268 AC: 565 AN: 2110

Alfa AF: 0.185 Hom.: 470

Bravo AF: 0.253

Asia WGS AF: 0.140 AC: 488 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.32
DANN	Benign	0.41
PhyloP100		-0.42
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: rs11168292; hg19: chr12-48293605;