chr16-46660189-G-GTTTTTTTTTTTTTTT

Variant names:

• chr16-46660189-G-GTTTTTTTTTTTTTTT
• rs369756092
• NM_018206.6:c.*282_*283insAAAAAAAAAAAAAAA

Variant summary

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

The NM_018206.6(VPS35):​c.*282_*283insAAAAAAAAAAAAAAA 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 0.000022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00047 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.37
• Publications: 2 publications found

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

ACMG classification

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.*282_*283insAAAAAAAAAAAAAAA		3_prime_UTR	Exon 17 of 17	NP_060676.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	ENST00000299138.12	TSL:1 MANE Select	c.*282_*283insAAAAAAAAAAAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAAAAAAAAAAAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAAAAAAAAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.0000223 AC: 2 AN: 89720 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000466 AC: 4 AN: 8590 Hom.: 2 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4408

African (AFR) AF: 0.00847 AC: 2 AN: 236

American (AMR) AF: 0.00297 AC: 2 AN: 674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 212

East Asian (EAS) AF: 0.00 AC: 0 AN: 360

South Asian (SAS) AF: 0.00 AC: 0 AN: 1332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4916

Other (OTH) AF: 0.00 AC: 0 AN: 476

GnomAD4 genome AF: 0.0000223 AC: 2 AN: 89720 Hom.: 0 Cov.: 0 AF XY: 0.0000250 AC XY: 1 AN XY: 39984

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

African (AFR) AF: 0.0000774 AC: 2 AN: 25828

American (AMR) AF: 0.00 AC: 0 AN: 6510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2560

East Asian (EAS) AF: 0.00 AC: 0 AN: 2272

South Asian (SAS) AF: 0.00 AC: 0 AN: 2152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47112

Other (OTH) AF: 0.00 AC: 0 AN: 1162

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs369756092; hg19: chr16-46694101;