16-46660189-G-GTTTTT

Variant names:

• chr16-46660189-G-GTTTTT
• rs369756092
• NM_018206.6:c.*282_*283insAAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_018206.6(VPS35):​c.*282_*283insAAAAA 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 0.0063 (82 hom., cov: 0)
  • Exomes 𝑓: 0.041 (108 hom.)
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0408 (350/8582) while in subpopulation MID AF = 0.0625 (2/32). AF 95% confidence interval is 0.0425. There are 108 homozygotes in GnomAdExome4. There are 198 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 82 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_*283insAAAAA		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_*283insAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 563 AN: 89696 Hom.: 81 Cov.: 0

Gnomad AFR AF: 0.00267

Gnomad AMI AF: 0.00500

Gnomad AMR AF: 0.00645

Gnomad ASJ AF: 0.00743

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.00419

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00749

Gnomad OTH AF: 0.00344

GnomAD4 exome AF: 0.0408 AC: 350 AN: 8582 Hom.: 108 Cov.: 0 AF XY: 0.0449 AC XY: 198 AN XY: 4406

African (AFR) AF: 0.00 AC: 0 AN: 236

American (AMR) AF: 0.0371 AC: 25 AN: 674

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 5 AN: 212

East Asian (EAS) AF: 0.0500 AC: 18 AN: 360

South Asian (SAS) AF: 0.0285 AC: 38 AN: 1332

European-Finnish (FIN) AF: 0.0426 AC: 15 AN: 352

Middle Eastern (MID) AF: 0.0625 AC: 2 AN: 32

European-Non Finnish (NFE) AF: 0.0475 AC: 233 AN: 4908

Other (OTH) AF: 0.0294 AC: 14 AN: 476

GnomAD4 genome AF: 0.00631 AC: 566 AN: 89710 Hom.: 82 Cov.: 0 AF XY: 0.00710 AC XY: 284 AN XY: 40008

African (AFR) AF: 0.00275 AC: 71 AN: 25838

American (AMR) AF: 0.00645 AC: 42 AN: 6514

Ashkenazi Jewish (ASJ) AF: 0.00743 AC: 19 AN: 2558

East Asian (EAS) AF: 0.0110 AC: 25 AN: 2270

South Asian (SAS) AF: 0.00466 AC: 10 AN: 2144

European-Finnish (FIN) AF: 0.0275 AC: 39 AN: 1416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.00749 AC: 353 AN: 47104

Other (OTH) AF: 0.00343 AC: 4 AN: 1166

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

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;