chr16-46660184-G-GTTT

Variant names:

• chr16-46660184-G-GTTT
• rs369068093
• NM_018206.6:c.*285_*287dupAAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_018206.6(VPS35):​c.*285_*287dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.013 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.25
• 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), Genomics England PanelApp, Ambry Genetics
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.*285_*287dupAAA		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.*285_*287dupAAA		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3346_*3348dupAAA		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3346_*3348dupAAA		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 296 AN: 22546 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00910

Gnomad AMI AF: 0.0467

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0125

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0221

GnomAD4 exome AF: 0.000244 AC: 11 AN: 45174 Hom.: 0 Cov.: 0 AF XY: 0.000263 AC XY: 6 AN XY: 22796

African (AFR) AF: 0.00 AC: 0 AN: 1854

American (AMR) AF: 0.00 AC: 0 AN: 2206

Ashkenazi Jewish (ASJ) AF: 0.000682 AC: 1 AN: 1466

East Asian (EAS) AF: 0.000401 AC: 1 AN: 2496

South Asian (SAS) AF: 0.000714 AC: 3 AN: 4200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.000215 AC: 6 AN: 27886

Other (OTH) AF: 0.00 AC: 0 AN: 2908

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0132 AC: 297 AN: 22558 Hom.: 0 Cov.: 27 AF XY: 0.0149 AC XY: 156 AN XY: 10494

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

African (AFR) AF: 0.00906 AC: 65 AN: 7176

American (AMR) AF: 0.0306 AC: 44 AN: 1436

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 7 AN: 562

East Asian (EAS) AF: 0.0296 AC: 24 AN: 810

South Asian (SAS) AF: 0.0232 AC: 25 AN: 1078

European-Finnish (FIN) AF: 0.0135 AC: 8 AN: 594

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

European-Non Finnish (NFE) AF: 0.0105 AC: 109 AN: 10428

Other (OTH) AF: 0.0219 AC: 5 AN: 228

⚠️ 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.

Alfa AF: 0.00166 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Parkinson Disease, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.3

Splicing

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

Other links and lift over

dbSNP: rs369068093; hg19: chr16-46694096;