16-46660189-G-GTTTT

Variant names:

• chr16-46660184-GTTTTG-GTTTT
• rs886052005
• NM_018206.6:c.*283delC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_018206.6(VPS35):​c.*283delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.090 (487 hom., cov: 12)
  • Exomes 𝑓: 0.0080 (42 hom.)
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.865
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 16-46660184-GTTTTG-GTTTT is Benign according to our data. Variant chr16-46660188-TG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319278.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 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.*283delC		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.*283delC		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3344delC		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3344delC		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 7873 AN: 87780 Hom.: 487 Cov.: 12

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0952

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0983

GnomAD4 exome AF: 0.00800 AC: 375 AN: 46904 Hom.: 42 Cov.: 0 AF XY: 0.00953 AC XY: 227 AN XY: 23814

African (AFR) AF: 0.00102 AC: 2 AN: 1960

American (AMR) AF: 0.00363 AC: 7 AN: 1926

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 3 AN: 1896

East Asian (EAS) AF: 0.00187 AC: 6 AN: 3212

South Asian (SAS) AF: 0.152 AC: 177 AN: 1164

European-Finnish (FIN) AF: 0.00594 AC: 13 AN: 2190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.00496 AC: 154 AN: 31074

Other (OTH) AF: 0.00400 AC: 13 AN: 3250

GnomAD4 genome AF: 0.0896 AC: 7871 AN: 87816 Hom.: 487 Cov.: 12 AF XY: 0.0915 AC XY: 3873 AN XY: 42318

African (AFR) AF: 0.0220 AC: 490 AN: 22318

American (AMR) AF: 0.0622 AC: 431 AN: 6926

Ashkenazi Jewish (ASJ) AF: 0.0952 AC: 218 AN: 2290

East Asian (EAS) AF: 0.108 AC: 379 AN: 3502

South Asian (SAS) AF: 0.412 AC: 1194 AN: 2898

European-Finnish (FIN) AF: 0.0654 AC: 261 AN: 3988

Middle Eastern (MID) AF: 0.0368 AC: 7 AN: 190

European-Non Finnish (NFE) AF: 0.106 AC: 4673 AN: 43928

Other (OTH) AF: 0.0970 AC: 105 AN: 1082

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: rs886052005; hg19: chr16-46694096;