16-46660189-G-GTTTTTTT

Variant names:

• chr16-46660189-G-GTTTTTTT
• rs369756092
• NM_018206.6:c.*282_*283insAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_018206.6(VPS35):​c.*282_*283insAAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (62 hom., cov: 0)
  • Exomes 𝑓: 0.096 (390 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -2 ACMG points.

• BP6: Variant 16-46660189-G-GTTTTTTT is Benign according to our data. Variant chr16-46660189-G-GTTTTTTT is described in ClinVar as Benign. ClinVar VariationId is 2646486.Status of the report is criteria_provided_single_submitter, 1 stars.

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_*283insAAAAAAA		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_*283insAAAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAAAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3343_*3344insAAAAAAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 318 AN: 89478 Hom.: 61 Cov.: 0

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00339

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.00196

Gnomad EAS AF: 0.00220

Gnomad SAS AF: 0.000930

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00431

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0956 AC: 821 AN: 8590 Hom.: 390 Cov.: 0 AF XY: 0.0937 AC XY: 413 AN XY: 4408

African (AFR) AF: 0.00424 AC: 1 AN: 236

American (AMR) AF: 0.148 AC: 100 AN: 674

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 21 AN: 212

East Asian (EAS) AF: 0.164 AC: 59 AN: 360

South Asian (SAS) AF: 0.0638 AC: 85 AN: 1332

European-Finnish (FIN) AF: 0.0966 AC: 34 AN: 352

Middle Eastern (MID) AF: 0.0938 AC: 3 AN: 32

European-Non Finnish (NFE) AF: 0.0968 AC: 476 AN: 4916

Other (OTH) AF: 0.0882 AC: 42 AN: 476

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00358 AC: 320 AN: 89492 Hom.: 62 Cov.: 0 AF XY: 0.00414 AC XY: 165 AN XY: 39890

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

African (AFR) AF: 0.00236 AC: 61 AN: 25808

American (AMR) AF: 0.00185 AC: 12 AN: 6502

Ashkenazi Jewish (ASJ) AF: 0.00196 AC: 5 AN: 2554

East Asian (EAS) AF: 0.00221 AC: 5 AN: 2266

South Asian (SAS) AF: 0.000933 AC: 2 AN: 2144

European-Finnish (FIN) AF: 0.0113 AC: 16 AN: 1416

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

European-Non Finnish (NFE) AF: 0.00452 AC: 212 AN: 46948

Other (OTH) AF: 0.00430 AC: 5 AN: 1164

⚠️ 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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;