NM_000376.3:c.1025-95G>A

Variant names:

• chr12-47845100-C-T
• rs11574114
• NM_000376.3:c.1025-95G>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.1025-95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,580,452 control chromosomes in the GnomAD database, including 2,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (627 hom., cov: 29)
  • Exomes 𝑓: 0.040 (1451 hom.)
• Consequence: VDR NM_000376.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.20
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-47845100-C-T is Benign according to our data. Variant chr12-47845100-C-T is described in ClinVar as Benign. ClinVar VariationId is 1251714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VDR	NM_000376.3	c.1025-95G>A		intron_variant	Intron 9 of 9	ENST00000549336.6	NP_000367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000549336.6	c.1025-95G>A		intron_variant	Intron 9 of 9	1	NM_000376.3	ENSP00000449573.2

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 10799 AN: 151186 Hom.: 621 Cov.: 29

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0603

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00333

Gnomad SAS AF: 0.0438

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0723

GnomAD4 exome AF: 0.0397 AC: 56806 AN: 1429148 Hom.: 1451 AF XY: 0.0396 AC XY: 28218 AN XY: 712236

African (AFR) AF: 0.166 AC: 5490 AN: 33086

American (AMR) AF: 0.0392 AC: 1746 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 545 AN: 25846

East Asian (EAS) AF: 0.00162 AC: 64 AN: 39616

South Asian (SAS) AF: 0.0420 AC: 3580 AN: 85138

European-Finnish (FIN) AF: 0.0610 AC: 2392 AN: 39236

Middle Eastern (MID) AF: 0.0585 AC: 244 AN: 4174

European-Non Finnish (NFE) AF: 0.0365 AC: 40067 AN: 1098022

Other (OTH) AF: 0.0450 AC: 2678 AN: 59530

GnomAD4 genome AF: 0.0716 AC: 10829 AN: 151304 Hom.: 627 Cov.: 29 AF XY: 0.0712 AC XY: 5261 AN XY: 73918

African (AFR) AF: 0.152 AC: 6239 AN: 41054

American (AMR) AF: 0.0601 AC: 916 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.00353 AC: 18 AN: 5098

South Asian (SAS) AF: 0.0436 AC: 208 AN: 4768

European-Finnish (FIN) AF: 0.0620 AC: 653 AN: 10536

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2510 AN: 67848

Other (OTH) AF: 0.0711 AC: 149 AN: 2096

Alfa AF: 0.0618 Hom.: 61

Bravo AF: 0.0762

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Sep 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.50
DANN	Benign	0.37
PhyloP100		-2.2
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: rs11574114; hg19: chr12-48238883;