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rs7975232

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000376.3(VDR):c.1025-49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 1,600,160 control chromosomes in the GnomAD database, including 225,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23205 hom., cov: 29)
Exomes 𝑓: 0.53 ( 202307 hom. )

Consequence

VDR
NM_000376.3 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: -0.874
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 12-47845054-C-A is Benign according to our data. Variant chr12-47845054-C-A is described in ClinVar as [Benign]. Clinvar id is 1252227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VDRNM_000376.3 linkuse as main transcriptc.1025-49G>T intron_variant ENST00000549336.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VDRENST00000549336.6 linkuse as main transcriptc.1025-49G>T intron_variant 1 NM_000376.3 P1P11473-1

Frequencies

GnomAD3 genomes
AF:
0.549
AC:
82955
AN:
151104
Hom.:
23182
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.627
Gnomad AMI
AF:
0.589
Gnomad AMR
AF:
0.504
Gnomad ASJ
AF:
0.583
Gnomad EAS
AF:
0.290
Gnomad SAS
AF:
0.559
Gnomad FIN
AF:
0.550
Gnomad MID
AF:
0.554
Gnomad NFE
AF:
0.528
Gnomad OTH
AF:
0.550
GnomAD3 exomes
AF:
0.511
AC:
123050
AN:
240798
Hom.:
32488
AF XY:
0.518
AC XY:
67861
AN XY:
130972
show subpopulations
Gnomad AFR exome
AF:
0.626
Gnomad AMR exome
AF:
0.410
Gnomad ASJ exome
AF:
0.570
Gnomad EAS exome
AF:
0.278
Gnomad SAS exome
AF:
0.577
Gnomad FIN exome
AF:
0.556
Gnomad NFE exome
AF:
0.534
Gnomad OTH exome
AF:
0.529
GnomAD4 exome
AF:
0.525
AC:
761265
AN:
1448938
Hom.:
202307
Cov.:
47
AF XY:
0.528
AC XY:
380601
AN XY:
721232
show subpopulations
Gnomad4 AFR exome
AF:
0.637
Gnomad4 AMR exome
AF:
0.423
Gnomad4 ASJ exome
AF:
0.567
Gnomad4 EAS exome
AF:
0.306
Gnomad4 SAS exome
AF:
0.576
Gnomad4 FIN exome
AF:
0.552
Gnomad4 NFE exome
AF:
0.527
Gnomad4 OTH exome
AF:
0.531
GnomAD4 genome
AF:
0.549
AC:
83031
AN:
151222
Hom.:
23205
Cov.:
29
AF XY:
0.549
AC XY:
40532
AN XY:
73840
show subpopulations
Gnomad4 AFR
AF:
0.627
Gnomad4 AMR
AF:
0.504
Gnomad4 ASJ
AF:
0.583
Gnomad4 EAS
AF:
0.290
Gnomad4 SAS
AF:
0.559
Gnomad4 FIN
AF:
0.550
Gnomad4 NFE
AF:
0.528
Gnomad4 OTH
AF:
0.552
Alfa
AF:
0.554
Hom.:
6048
Bravo
AF:
0.545
Asia WGS
AF:
0.468
AC:
1628
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Pathogenic:1Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedcase-controlBioengineering and Technology, Gauhati UniversityJul 14, 2022- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxAug 16, 2018- -
Vitamin D-dependent rickets type II with alopecia Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
Periodontitis Benign:1
Benign, no assertion criteria providedcase-controlGenetics Laboratory, Lanzhou UniversityApr 20, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
Cadd
Benign
2.5
Dann
Benign
0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs7975232; hg19: chr12-48238837; COSMIC: COSV57467972; API