rs168745

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_018206.6(VPS35):c.1938C>T(p.His646His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,194 control chromosomes in the GnomAD database, including 800,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.98 ( 72733 hom., cov: 32)

Exomes 𝑓: 1.0 ( 727643 hom. )

Consequence

VPS35
NM_018206.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.341

Publications

25 publications found

Variant links:

Genes affected

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

VPS35 Gene-Disease associations (from GenCC):

Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Parkinson disease 17
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

VPS35 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 16-46662372-G-A is Benign according to our data. Variant chr16-46662372-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.341 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VPS35	NM_018206.6 link	c.1938C>T	p.His646His	synonymous_variant	Exon 15 of 17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4 link	c.1851C>T	p.His617His	synonymous_variant	Exon 15 of 17		XP_011521529.1
VPS35	XM_005256045.4 link	c.1737C>T	p.His579His	synonymous_variant	Exon 13 of 15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12 link	c.1938C>T	p.His646His	synonymous_variant	Exon 15 of 17	1	NM_018206.6	ENSP00000299138.7

Frequencies

GnomAD3 genomes

AF:

0.977

AC:

148661

AN:

152186

Hom.:

72688

Cov.:

show subpopulations

Gnomad AFR

AF:

0.919

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.992

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.982

GnomAD2 exomes

AF:

0.994

AC:

249749

AN:

251282

AF XY:

0.996

show subpopulations

Gnomad AFR exome

AF:

0.917

Gnomad AMR exome

AF:

0.996

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.998

GnomAD4 exome

AF:

0.998

AC:

1458489

AN:

1461890

Hom.:

727643

Cov.:

AF XY:

0.998

AC XY:

725836

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.917

AC:

30709

AN:

33480

American (AMR)

AF:

0.995

AC:

44501

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26129

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39696

AN:

39696

South Asian (SAS)

AF:

1.00

AC:

86232

AN:

86258

European-Finnish (FIN)

AF:

1.00

AC:

53420

AN:

53420

Middle Eastern (MID)

AF:

0.999

AC:

5760

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111957

AN:

1112012

Other (OTH)

AF:

0.995

AC:

60085

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

233

466

700

933

1166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.977

AC:

148763

AN:

152304

Hom.:

72733

Cov.:

AF XY:

0.977

AC XY:

72764

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.919

AC:

38181

AN:

41540

American (AMR)

AF:

0.992

AC:

15178

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

3470

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5188

AN:

5188

South Asian (SAS)

AF:

1.00

AC:

4818

AN:

4820

European-Finnish (FIN)

AF:

1.00

AC:

10626

AN:

10626

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68023

AN:

68036

Other (OTH)

AF:

0.982

AC:

2074

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

172

344

515

687

859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.989

Hom.:

38604

Bravo

AF:

0.973

Asia WGS

AF:

0.997

AC:

3466

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Parkinson disease 17

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

3.5

(source)

DANN

Benign

0.71

PhyloP100

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=99/1

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over