Genetic Variant VPS35:c.*285_*287dupAAA (chr16-46660184-G-GTTT) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018206.6(VPS35):c.*285_*287dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.013 ( 0 hom., cov: 27)

Exomes 𝑓: 0.00024 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VPS35
NM_018206.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.25

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

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.285_287dupAAA		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.285_287dupAAA	3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
VPS35	ENST00000568784.6	TSL:1	n.3346_3348dupAAA	non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
VPS35	ENST00000568784.6	TSL:1	n.3346_3348dupAAA	3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

296

AN:

22546

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00910

Gnomad AMI

AF:

0.0467

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0125

Gnomad EAS

AF:

0.0296

Gnomad SAS

AF:

0.0220

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0221

GnomAD4 exome

AF:

0.000244

AC:

AN:

45174

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

22796

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

1854

American (AMR)

AF:

0.00

AC:

AN:

2206

Ashkenazi Jewish (ASJ)

AF:

0.000682

AC:

AN:

1466

East Asian (EAS)

AF:

0.000401

AC:

AN:

2496

South Asian (SAS)

AF:

0.000714

AC:

AN:

4200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.000215

AC:

AN:

27886

Other (OTH)

AF:

0.00

AC:

AN:

2908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0132

AC:

297

AN:

22558

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

156

AN XY:

10494

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00906

AC:

AN:

7176

American (AMR)

AF:

0.0306

AC:

AN:

1436

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

AN:

562

East Asian (EAS)

AF:

0.0296

AC:

AN:

810

South Asian (SAS)

AF:

0.0232

AC:

AN:

1078

European-Finnish (FIN)

AF:

0.0135

AC:

AN:

594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0105

AC:

109

AN:

10428

Other (OTH)

AF:

0.0219

AC:

AN:

228

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00166

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.3

Splicing

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

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