Genetic Variant NM_018206.6:c.*282_*283insAA (chr16-46660189-G-GTT) – 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_*283insAA 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 0.085 ( 713 hom., cov: 0)

Exomes 𝑓: 0.084 ( 295 hom. )

Failed GnomAD Quality Control

Consequence

VPS35
NM_018206.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.37

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

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.103 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_283insAA		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_283insAA	3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAA	non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAA	3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes

AF:

0.0849

AC:

7617

AN:

89758

Hom.:

710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0463

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.0734

Gnomad ASJ

AF:

0.0622

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.0856

Gnomad MID

AF:

0.0943

Gnomad NFE

AF:

0.114

Gnomad OTH

AF:

0.0947

GnomAD4 exome

AF:

0.0842

AC:

720

AN:

8548

Hom.:

295

Cov.:

AF XY:

0.0855

AC XY:

375

AN XY:

4384

show subpopulations

African (AFR)

AF:

0.0339

AC:

AN:

236

American (AMR)

AF:

0.0952

AC:

AN:

672

Ashkenazi Jewish (ASJ)

AF:

0.0613

AC:

AN:

212

East Asian (EAS)

AF:

0.0472

AC:

AN:

360

South Asian (SAS)

AF:

0.0589

AC:

AN:

1324

European-Finnish (FIN)

AF:

0.0743

AC:

AN:

350

Middle Eastern (MID)

AF:

0.219

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0943

AC:

461

AN:

4890

Other (OTH)

AF:

0.0975

AC:

AN:

472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0849

AC:

7619

AN:

89772

Hom.:

713

Cov.:

AF XY:

0.0809

AC XY:

3240

AN XY:

40026

show subpopulations

African (AFR)

AF:

0.0465

AC:

1201

AN:

25852

American (AMR)

AF:

0.0737

AC:

480

AN:

6514

Ashkenazi Jewish (ASJ)

AF:

0.0622

AC:

159

AN:

2556

East Asian (EAS)

AF:

0.0101

AC:

AN:

2268

South Asian (SAS)

AF:

0.0182

AC:

AN:

2146

European-Finnish (FIN)

AF:

0.0856

AC:

121

AN:

1414

Middle Eastern (MID)

AF:

0.0600

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.114

AC:

5397

AN:

47154

Other (OTH)

AF:

0.0961

AC:

112

AN:

1166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

233

466

698

931

1164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_018206.6:c.282_283insAA

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