Genetic Variant VPS52:p.Leu274Leu (chr6-33267978-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_022553.6(VPS52):c.820C>T(p.Leu274Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,612,704 control chromosomes in the GnomAD database, including 115,248 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 0.40 ( 12214 hom., cov: 31)

Exomes 𝑓: 0.37 ( 103034 hom. )

Consequence

VPS52
NM_022553.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.38

Publications

33 publications found

Variant links:

Genes affected

VPS52 (HGNC:10518): (VPS52 subunit of GARP complex) This gene encodes a protein that is similar to the yeast suppressor of actin mutations 2 gene. The yeast protein forms a subunit of the tetrameric Golgi-associated retrograde protein complex that is involved in vesicle trafficking from from both early and late endosomes, back to the trans-Golgi network. This gene is located on chromosome 6 in a head-to-head orientation with the gene encoding ribosomal protein S18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

VPS52 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP7

Synonymous conserved (PhyloP=2.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS52	NM_022553.6 link	c.820C>T	p.Leu274Leu	synonymous_variant	Exon 9 of 20	ENST00000445902.3	NP_072047.4	Q8N1B4-1B3KMF7Q4VXZ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS52	ENST00000445902.3 link	c.820C>T	p.Leu274Leu	synonymous_variant	Exon 9 of 20	1	NM_022553.6	ENSP00000409952.2		Q8N1B4-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60340

AN:

151798

Hom.:

12210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.431

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.427

Gnomad EAS

AF:

0.601

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.423

GnomAD2 exomes

AF:

0.389

AC:

95927

AN:

246752

AF XY:

0.388

show subpopulations

Gnomad AFR exome

AF:

0.432

Gnomad AMR exome

AF:

0.338

Gnomad ASJ exome

AF:

0.435

Gnomad EAS exome

AF:

0.626

Gnomad FIN exome

AF:

0.397

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.383

GnomAD4 exome

AF:

0.371

AC:

542215

AN:

1460788

Hom.:

103034

Cov.:

AF XY:

0.372

AC XY:

270054

AN XY:

726706

show subpopulations

African (AFR)

AF:

0.446

AC:

14943

AN:

33480

American (AMR)

AF:

0.348

AC:

15559

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.431

AC:

11275

AN:

26136

East Asian (EAS)

AF:

0.646

AC:

25627

AN:

39700

South Asian (SAS)

AF:

0.381

AC:

32902

AN:

86258

European-Finnish (FIN)

AF:

0.395

AC:

20663

AN:

52334

Middle Eastern (MID)

AF:

0.428

AC:

2470

AN:

5768

European-Non Finnish (NFE)

AF:

0.356

AC:

395907

AN:

1112002

Other (OTH)

AF:

0.379

AC:

22869

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

22097

44195

66292

88390

110487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12678

25356

38034

50712

63390

<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:

0.397

AC:

60362

AN:

151916

Hom.:

12214

Cov.:

AF XY:

0.397

AC XY:

29497

AN XY:

74230

show subpopulations

African (AFR)

AF:

0.431

AC:

17835

AN:

41402

American (AMR)

AF:

0.379

AC:

5784

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.427

AC:

1478

AN:

3464

East Asian (EAS)

AF:

0.601

AC:

3106

AN:

5164

South Asian (SAS)

AF:

0.384

AC:

1847

AN:

4814

European-Finnish (FIN)

AF:

0.401

AC:

4223

AN:

10534

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.364

AC:

24740

AN:

67966

Other (OTH)

AF:

0.425

AC:

892

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1874

3747

5621

7494

9368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

578

1156

1734

2312

2890

<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:

0.376

Hom.:

23674

Bravo

AF:

0.399

Asia WGS

AF:

0.484

AC:

1682

AN:

3478

EpiCase

AF:

0.364

EpiControl

AF:

0.372

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.4

(source)

DANN

Benign

0.83

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over