Genetic Variant VPS35:c.*282_*283insAAAAAA (chr16-46660189-G-GTTTTTT) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_018206.6(VPS35):c.*282_*283insAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 52 hom., cov: 0)

Exomes 𝑓: 0.22 ( 897 hom. )

Failed GnomAD Quality Control

Consequence

VPS35
NM_018206.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

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), 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 16-46660189-G-GTTTTTT is Benign according to our data. Variant chr16-46660189-G-GTTTTTT is described in ClinVar as Likely_benign. ClinVar VariationId is 1711407.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 52 AD,AR gene

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_283insAAAAAA		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_283insAAAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAAAAAA	non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAAAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes

AF:

0.00269

AC:

241

AN:

89586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.00167

Gnomad AMR

AF:

0.00323

Gnomad ASJ

AF:

0.00156

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00139

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00174

Gnomad OTH

AF:

0.00258

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.217

AC:

1864

AN:

8590

Hom.:

897

Cov.:

AF XY:

0.216

AC XY:

954

AN XY:

4408

show subpopulations

African (AFR)

AF:

0.0678

AC:

AN:

236

American (AMR)

AF:

0.257

AC:

173

AN:

674

Ashkenazi Jewish (ASJ)

AF:

0.212

AC:

AN:

212

East Asian (EAS)

AF:

0.314

AC:

113

AN:

360

South Asian (SAS)

AF:

0.140

AC:

187

AN:

1332

European-Finnish (FIN)

AF:

0.270

AC:

AN:

352

Middle Eastern (MID)

AF:

0.125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.229

AC:

1126

AN:

4916

Other (OTH)

AF:

0.221

AC:

105

AN:

476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.672

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:

0.00273

AC:

245

AN:

89600

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

141

AN XY:

39942

show subpopulations

African (AFR)

AF:

0.00396

AC:

102

AN:

25752

American (AMR)

AF:

0.00322

AC:

AN:

6512

Ashkenazi Jewish (ASJ)

AF:

0.00156

AC:

AN:

2560

East Asian (EAS)

AF:

0.00309

AC:

AN:

2268

South Asian (SAS)

AF:

0.00140

AC:

AN:

2146

European-Finnish (FIN)

AF:

0.0155

AC:

AN:

1418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.00174

AC:

AN:

47078

Other (OTH)

AF:

0.00257

AC:

AN:

1166

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

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

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