Genetic Variant NM_018206.6:c.*282_*283insAAAAAAAAAAA (chr16-46660189-G-GTTTTTTTTTTT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_018206.6(VPS35):c.*282_*283insAAAAAAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00029 ( 7 hom., cov: 0)

Exomes 𝑓: 0.0029 ( 10 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 7 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_283insAAAAAAAAAAA		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_283insAAAAAAAAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAAAAAAAAAAA	non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
VPS35	ENST00000568784.6	TSL:1	n.3343_3344insAAAAAAAAAAA	3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes

AF:

0.000290

AC:

AN:

89710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000307

Gnomad ASJ

AF:

0.000391

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00279

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000234

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00291

AC:

AN:

8590

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

AN XY:

4408

show subpopulations

African (AFR)

AF:

0.00847

AC:

AN:

236

American (AMR)

AF:

0.00

AC:

AN:

674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

212

East Asian (EAS)

AF:

0.00

AC:

AN:

360

South Asian (SAS)

AF:

0.0128

AC:

AN:

1332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

4916

Other (OTH)

AF:

0.00

AC:

AN:

476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

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:

0.000290

AC:

AN:

89724

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

AN XY:

40006

show subpopulations

African (AFR)

AF:

0.000155

AC:

AN:

25854

American (AMR)

AF:

0.000307

AC:

AN:

6516

Ashkenazi Jewish (ASJ)

AF:

0.000391

AC:

AN:

2560

East Asian (EAS)

AF:

0.00

AC:

AN:

2268

South Asian (SAS)

AF:

0.00280

AC:

AN:

2146

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

1418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

100

European-Non Finnish (NFE)

AF:

0.000234

AC:

AN:

47096

Other (OTH)

AF:

0.00

AC:

AN:

1166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

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

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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NM_018206.6:c.282_283insAAAAAAAAAAA

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