Genetic Variant NM_000376.3:c.1056T>C (chr12-47844974-A-G) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is . The variant received -17 classification points (ACMG Germline Pathogenicity v2019): 0P and 17B. BA1BP4_StrongBP6_StrongBP7

The NM_000376.3(VDR):c.1056T>C (p.Ile352Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.372 (AC=600,623) in the gnomAD database across 1,613,190 control chromosomes, including 115,868 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.4. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9106 hom., cov: 31)

Exomes 𝑓: 0.38 ( 106762 hom. )

Consequence

VDR
NM_000376.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: -2.46

Publications

1160 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, PanelApp Australia
vitamin D-dependent rickets, type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VDR links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000376.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -17 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BP7

Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4000 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000376.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VDR	NM_000376.3	MANE Select	c.1056T>C	p.Ile352Ile	synonymous	Exon 10 of 10	NP_000367.1	P11473-1
VDR	NM_001364085.2		c.1056T>C	p.Ile352Ile	synonymous	Exon 10 of 10	NP_001351014.1	A0A5K1VW50
VDR	NM_001017536.2		c.1206T>C	p.Ile402Ile	synonymous	Exon 10 of 10	NP_001017536.1	P11473-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VDR	ENST00000549336.6	TSL:1 MANE Select	c.1056T>C	p.Ile352Ile	synonymous	Exon 10 of 10	ENSP00000449573.2	P11473-1
VDR	ENST00000550325.5	TSL:1	c.1206T>C	p.Ile402Ile	synonymous	Exon 10 of 10	ENSP00000447173.1	P11473-2
VDR	ENST00000229022.9	TSL:5	c.1056T>C	p.Ile352Ile	synonymous	Exon 8 of 8	ENSP00000229022.5	A0A5K1VW50

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51104

AN:

151662

Hom.:

9108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.277

Gnomad AMR

AF:

0.303

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.0619

Gnomad SAS

AF:

0.331

Gnomad FIN

AF:

0.330

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.397

Gnomad OTH

AF:

0.349

GnomAD2 exomes

AF:

0.327

AC:

82106

AN:

250982

AF XY:

0.337

show subpopulations

Gnomad AFR exome

AF:

0.276

Gnomad AMR exome

AF:

0.213

Gnomad ASJ exome

AF:

0.359

Gnomad EAS exome

AF:

0.0540

Gnomad FIN exome

AF:

0.330

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.360

GnomAD4 exome

AF:

0.376

AC:

549510

AN:

1461414

Hom.:

106762

Cov.:

AF XY:

0.376

AC XY:

273622

AN XY:

727036

show subpopulations

African (AFR)

AF:

0.280

AC:

9378

AN:

33478

American (AMR)

AF:

0.224

AC:

10004

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.358

AC:

9362

AN:

26130

East Asian (EAS)

AF:

0.0849

AC:

3371

AN:

39684

South Asian (SAS)

AF:

0.347

AC:

29930

AN:

86258

European-Finnish (FIN)

AF:

0.332

AC:

17601

AN:

53050

Middle Eastern (MID)

AF:

0.412

AC:

2367

AN:

5746

European-Non Finnish (NFE)

AF:

0.401

AC:

445934

AN:

1111970

Other (OTH)

AF:

0.357

AC:

21563

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

23525

47050

70576

94101

117626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13554

27108

40662

54216

67770

<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:

0.337

AC:

51113

AN:

151776

Hom.:

9106

Cov.:

AF XY:

0.332

AC XY:

24617

AN XY:

74150

show subpopulations

African (AFR)

AF:

0.286

AC:

11842

AN:

41388

American (AMR)

AF:

0.303

AC:

4611

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1243

AN:

3466

East Asian (EAS)

AF:

0.0622

AC:

320

AN:

5142

South Asian (SAS)

AF:

0.330

AC:

1585

AN:

4810

European-Finnish (FIN)

AF:

0.330

AC:

3479

AN:

10530

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.397

AC:

26940

AN:

67886

Other (OTH)

AF:

0.350

AC:

738

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1706

3412

5118

6824

8530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.375

Hom.:

33940

Bravo

AF:

0.327

Asia WGS

AF:

0.220

AC:

765

AN:

3478

EpiCase

AF:

0.406

EpiControl

AF:

0.402

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.114

AC:

13903

AN:

121902

Turkish Variome

AF:

0.366

AC:

2457

AN:

6718

Hom.:

472

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0530

AC:

475

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.352

AC:

824

AN:

2342

Hom.:

151

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Vitamin D-dependent rickets type II with alopecia (2)

Periodontitis (1)

Hepatocellular carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.030

(source)

DANN

Benign

0.49

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over