Genetic Variant VPS35:c.*284_*287dupAAAA (chr16-46660184-G-GTTTT) – 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.*284_*287dupAAAA 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 0.0016 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000066 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

VPS35
NM_018206.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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), Genomics England PanelApp, Ambry Genetics
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.284_287dupAAAA		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.284_287dupAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
VPS35	ENST00000568784.6	TSL:1	n.3345_3348dupAAAA	non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
VPS35	ENST00000568784.6	TSL:1	n.3345_3348dupAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

AN:

22854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00410

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0124

Gnomad SAS

AF:

0.000909

Gnomad FIN

AF:

0.00330

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000664

AC:

AN:

45174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

22798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

1854

American (AMR)

AF:

0.00

AC:

AN:

2208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1466

East Asian (EAS)

AF:

0.00

AC:

AN:

2496

South Asian (SAS)

AF:

0.00

AC:

AN:

4198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.000108

AC:

AN:

27886

Other (OTH)

AF:

0.00

AC:

AN:

2908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00157

AC:

AN:

22868

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

AN XY:

10660

show subpopulations

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

African (AFR)

AF:

0.000138

AC:

AN:

7240

American (AMR)

AF:

0.00342

AC:

AN:

1464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

574

East Asian (EAS)

AF:

0.0124

AC:

AN:

804

South Asian (SAS)

AF:

0.000919

AC:

AN:

1088

European-Finnish (FIN)

AF:

0.00330

AC:

AN:

606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00160

AC:

AN:

10602

Other (OTH)

AF:

0.00

AC:

AN:

238

⚠️ 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: 0.303

Heterozygous variant carriers

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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over