Genetic Variant VPS35:c.*282_*283insAAAA (chr16-46660189-G-GTTTT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_018206.6(VPS35):c.*282_*283insAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.082 ( 760 hom., cov: 0)

Exomes 𝑓: 0.072 ( 225 hom. )

Consequence

VPS35
NM_018206.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.37

Publications

2 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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	NM_018206.6	MANE Select	c.282_283insAAAA		3_prime_UTR	Exon 17 of 17	NP_060676.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VPS35	ENST00000299138.12	TSL:1 MANE Select	c.282_283insAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAAAA	non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes

AF:

0.0819

AC:

7345

AN:

89680

Hom.:

761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0250

Gnomad AMR

AF:

0.0897

Gnomad ASJ

AF:

0.0647

Gnomad EAS

AF:

0.309

Gnomad SAS

AF:

0.0924

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.0189

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.0871

GnomAD4 exome

AF:

0.0719

AC:

617

AN:

8576

Hom.:

225

Cov.:

AF XY:

0.0660

AC XY:

291

AN XY:

4406

show subpopulations

African (AFR)

AF:

0.0424

AC:

AN:

236

American (AMR)

AF:

0.0579

AC:

AN:

674

Ashkenazi Jewish (ASJ)

AF:

0.0755

AC:

AN:

212

East Asian (EAS)

AF:

0.0583

AC:

AN:

360

South Asian (SAS)

AF:

0.0557

AC:

AN:

1328

European-Finnish (FIN)

AF:

0.0767

AC:

AN:

352

Middle Eastern (MID)

AF:

0.0313

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0779

AC:

382

AN:

4906

Other (OTH)

AF:

0.0987

AC:

AN:

476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.543

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:

0.0818

AC:

7341

AN:

89694

Hom.:

760

Cov.:

AF XY:

0.0804

AC XY:

3216

AN XY:

39988

show subpopulations

African (AFR)

AF:

0.0231

AC:

597

AN:

25810

American (AMR)

AF:

0.0893

AC:

582

AN:

6516

Ashkenazi Jewish (ASJ)

AF:

0.0647

AC:

165

AN:

2552

East Asian (EAS)

AF:

0.309

AC:

707

AN:

2286

South Asian (SAS)

AF:

0.0922

AC:

197

AN:

2136

European-Finnish (FIN)

AF:

0.125

AC:

176

AN:

1410

Middle Eastern (MID)

AF:

0.0200

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.102

AC:

4799

AN:

47120

Other (OTH)

AF:

0.0868

AC:

101

AN:

1164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

231

462

692

923

1154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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