16-46660189-G-GTTT

Variant names:

• chr16-46660189-G-GTTT
• rs369756092
• NM_018206.6:c.*282_*283insAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_018206.6(VPS35):​c.*282_*283insAAA 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 0.49 (11408 hom., cov: 0)
  • Exomes 𝑓: 0.12 (410 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.124 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_*283insAAA		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_*283insAAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.494 AC: 44289 AN: 89700 Hom.: 11403 Cov.: 0

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.609

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.520

GnomAD4 exome AF: 0.122 AC: 1041 AN: 8556 Hom.: 410 Cov.: 0 AF XY: 0.122 AC XY: 534 AN XY: 4388

African (AFR) AF: 0.0339 AC: 8 AN: 236

American (AMR) AF: 0.110 AC: 74 AN: 672

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 31 AN: 210

East Asian (EAS) AF: 0.0778 AC: 28 AN: 360

South Asian (SAS) AF: 0.116 AC: 153 AN: 1324

European-Finnish (FIN) AF: 0.108 AC: 38 AN: 352

Middle Eastern (MID) AF: 0.125 AC: 4 AN: 32

European-Non Finnish (NFE) AF: 0.133 AC: 650 AN: 4894

Other (OTH) AF: 0.116 AC: 55 AN: 476

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.494 AC: 44298 AN: 89718 Hom.: 11408 Cov.: 0 AF XY: 0.484 AC XY: 19337 AN XY: 39960

African (AFR) AF: 0.440 AC: 11302 AN: 25668

American (AMR) AF: 0.565 AC: 3687 AN: 6524

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 1578 AN: 2592

East Asian (EAS) AF: 0.421 AC: 961 AN: 2280

South Asian (SAS) AF: 0.510 AC: 1074 AN: 2106

European-Finnish (FIN) AF: 0.359 AC: 507 AN: 1412

Middle Eastern (MID) AF: 0.676 AC: 69 AN: 102

European-Non Finnish (NFE) AF: 0.512 AC: 24197 AN: 47258

Other (OTH) AF: 0.521 AC: 609 AN: 1170

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;