16-46660189-G-GTTTTTTTT

Variant names:

• chr16-46660189-G-GTTTTTTTT
• rs369756092
• NM_018206.6:c.*282_*283insAAAAAAAA

Variant summary

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

The NM_018206.6(VPS35):​c.*282_*283insAAAAAAAA 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 0.022 (119 hom., cov: 0)
  • Exomes 𝑓: 0.031 (122 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 119 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_*283insAAAAAAAA		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_*283insAAAAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAAAAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 1863 AN: 86404 Hom.: 119 Cov.: 0

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0348

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0319

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0257

Gnomad OTH AF: 0.0167

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0312 AC: 268 AN: 8586 Hom.: 122 Cov.: 0 AF XY: 0.0320 AC XY: 141 AN XY: 4406

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

American (AMR) AF: 0.0491 AC: 33 AN: 672

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 9 AN: 210

East Asian (EAS) AF: 0.0750 AC: 27 AN: 360

South Asian (SAS) AF: 0.0195 AC: 26 AN: 1332

European-Finnish (FIN) AF: 0.0199 AC: 7 AN: 352

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

European-Non Finnish (NFE) AF: 0.0323 AC: 159 AN: 4916

Other (OTH) AF: 0.0105 AC: 5 AN: 476

GnomAD4 genome AF: 0.0216 AC: 1865 AN: 86420 Hom.: 119 Cov.: 0 AF XY: 0.0226 AC XY: 873 AN XY: 38574

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

African (AFR) AF: 0.0158 AC: 398 AN: 25264

American (AMR) AF: 0.0180 AC: 114 AN: 6316

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 76 AN: 2380

East Asian (EAS) AF: 0.0244 AC: 54 AN: 2210

South Asian (SAS) AF: 0.00898 AC: 19 AN: 2116

European-Finnish (FIN) AF: 0.00923 AC: 13 AN: 1408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.0257 AC: 1153 AN: 44940

Other (OTH) AF: 0.0166 AC: 19 AN: 1144

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), 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
Mutation Taster		=100/0	polymorphism

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs369756092; hg19: chr16-46694101;