Genetic Variant ENST00000395324.6:c.-84+27T>G (chr12-47942836-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000395324.6(VDR):c.-84+27T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 149,642 control chromosomes in the GnomAD database, including 27,030 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 26821 hom., cov: 25)

Exomes 𝑓: 0.59 ( 209 hom. )

Consequence

VDR
ENST00000395324.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.338

Publications

8 publications found

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]

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

VDR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VDR	ENST00000395324.6 link	c.-84+27T>G		intron_variant	Intron 1 of 9	5		ENSP00000378734.2		P11473-1

Frequencies

GnomAD3 genomes

AF:

0.600

AC:

89001

AN:

148458

Hom.:

26788

Cov.:

show subpopulations

Gnomad AFR

AF:

0.554

Gnomad AMI

AF:

0.699

Gnomad AMR

AF:

0.670

Gnomad ASJ

AF:

0.601

Gnomad EAS

AF:

0.528

Gnomad SAS

AF:

0.638

Gnomad FIN

AF:

0.660

Gnomad MID

AF:

0.558

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.573

GnomAD4 exome

AF:

0.593

AC:

632

AN:

1066

Hom.:

209

Cov.:

AF XY:

0.586

AC XY:

429

AN XY:

732

show subpopulations

African (AFR)

AF:

0.700

AC:

AN:

American (AMR)

AF:

0.667

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

AN:

East Asian (EAS)

AF:

0.300

AC:

AN:

South Asian (SAS)

AF:

0.474

AC:

AN:

European-Finnish (FIN)

AF:

0.662

AC:

200

AN:

302

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.568

AC:

358

AN:

630

Other (OTH)

AF:

0.591

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.600

AC:

89085

AN:

148576

Hom.:

26821

Cov.:

AF XY:

0.603

AC XY:

43682

AN XY:

72406

show subpopulations

African (AFR)

AF:

0.553

AC:

22216

AN:

40142

American (AMR)

AF:

0.671

AC:

10022

AN:

14944

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

2066

AN:

3438

East Asian (EAS)

AF:

0.529

AC:

2605

AN:

4928

South Asian (SAS)

AF:

0.639

AC:

2973

AN:

4656

European-Finnish (FIN)

AF:

0.660

AC:

6726

AN:

10190

Middle Eastern (MID)

AF:

0.562

AC:

163

AN:

290

European-Non Finnish (NFE)

AF:

0.604

AC:

40496

AN:

67028

Other (OTH)

AF:

0.578

AC:

1192

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1618

3236

4855

6473

8091

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.598

Hom.:

3391

Bravo

AF:

0.598

Asia WGS

AF:

0.620

AC:

2151

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

1.5

(source)

DANN

Benign

0.23

PhyloP100

0.34

PromoterAI

-0.050

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over