rs10783218

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000376.3(VDR):c.146+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 1,614,062 control chromosomes in the GnomAD database, including 2,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 751 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1743 hom. )

Consequence

VDR
NM_000376.3 splice_region, intron

Scores

Splicing: ADA: 0.0001908

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.85

Publications

20 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: G2P, Labcorp Genetics (formerly Invitae)
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 12-47878960-G-A is Benign according to our data. Variant chr12-47878960-G-A is described in ClinVar as Benign. ClinVar VariationId is 308886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VDR	NM_000376.3	MANE Select	c.146+8C>T	splice_region intron	N/A	NP_000367.1	P11473-1
VDR	NM_001364085.2		c.146+8C>T	splice_region intron	N/A	NP_001351014.1	A0A5K1VW50
VDR	NM_001017536.2		c.296+8C>T	splice_region intron	N/A	NP_001017536.1	P11473-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VDR	ENST00000549336.6	TSL:1 MANE Select	c.146+8C>T	splice_region intron	N/A	ENSP00000449573.2	P11473-1
VDR	ENST00000550325.5	TSL:1	c.296+8C>T	splice_region intron	N/A	ENSP00000447173.1	P11473-2
VDR	ENST00000229022.9	TSL:5	c.146+8C>T	splice_region intron	N/A	ENSP00000229022.5	A0A5K1VW50

Frequencies

GnomAD3 genomes

AF:

0.0744

AC:

11316

AN:

152090

Hom.:

746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0369

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.0487

Gnomad SAS

AF:

0.0450

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0359

Gnomad OTH

AF:

0.0703

GnomAD2 exomes

AF:

0.0450

AC:

11311

AN:

251350

AF XY:

0.0431

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.0221

Gnomad ASJ exome

AF:

0.0220

Gnomad EAS exome

AF:

0.0486

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.0368

Gnomad OTH exome

AF:

0.0381

GnomAD4 exome

AF:

0.0422

AC:

61654

AN:

1461854

Hom.:

1743

Cov.:

AF XY:

0.0421

AC XY:

30605

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.193

AC:

6476

AN:

33476

American (AMR)

AF:

0.0235

AC:

1052

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

587

AN:

26136

East Asian (EAS)

AF:

0.0550

AC:

2185

AN:

39698

South Asian (SAS)

AF:

0.0494

AC:

4265

AN:

86254

European-Finnish (FIN)

AF:

0.0236

AC:

1260

AN:

53402

Middle Eastern (MID)

AF:

0.0609

AC:

351

AN:

5768

European-Non Finnish (NFE)

AF:

0.0383

AC:

42587

AN:

1112004

Other (OTH)

AF:

0.0479

AC:

2891

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

3692

7384

11077

14769

18461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1748

3496

5244

6992

8740

<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:

0.0745

AC:

11339

AN:

152208

Hom.:

751

Cov.:

AF XY:

0.0720

AC XY:

5356

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.178

AC:

7393

AN:

41498

American (AMR)

AF:

0.0367

AC:

562

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3472

East Asian (EAS)

AF:

0.0486

AC:

252

AN:

5180

South Asian (SAS)

AF:

0.0452

AC:

218

AN:

4822

European-Finnish (FIN)

AF:

0.0192

AC:

204

AN:

10618

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0359

AC:

2443

AN:

67992

Other (OTH)

AF:

0.0691

AC:

146

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

505

1010

1514

2019

2524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0497

Hom.:

759

Bravo

AF:

0.0801

Asia WGS

AF:

0.0590

AC:

204

AN:

3478

EpiCase

AF:

0.0384

EpiControl

AF:

0.0386

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Vitamin D-dependent rickets type II with alopecia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.97

(source)

DANN

Benign

0.71

PhyloP100

-1.8

PromoterAI

0.0021

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over