16-46659709-CAA-CAAA

Variant names:

• chr16-46659709-C-CA
• rs34926621
• NM_018206.6:c.*762dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_018206.6(VPS35):​c.*762dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 143,222 control chromosomes in the GnomAD database, including 1,413 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (1413 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.88
• Publications: 4 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 16-46659709-C-CA is Benign according to our data. Variant chr16-46659709-C-CA is described in ClinVar as Likely_benign. ClinVar VariationId is 319266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.274 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.*762dupT		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.*762dupT		3_prime_UTR	Exon 17 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000568784.6	TSL:1	n.*3823dupT		non_coding_transcript_exon	Exon 17 of 17	ENSP00000456274.2	H3BRJ7
	VPS35	ENST00000568784.6	TSL:1	n.*3823dupT		3_prime_UTR	Exon 17 of 17	ENSP00000456274.2	H3BRJ7

Frequencies

GnomAD3 genomes AF: 0.127 AC: 18111 AN: 143154 Hom.: 1405 Cov.: 30

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0646

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.126

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.127 AC: 18136 AN: 143222 Hom.: 1413 Cov.: 30 AF XY: 0.128 AC XY: 8860 AN XY: 69468

African (AFR) AF: 0.0344 AC: 1330 AN: 38622

American (AMR) AF: 0.230 AC: 3356 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 375 AN: 3354

East Asian (EAS) AF: 0.286 AC: 1447 AN: 5052

South Asian (SAS) AF: 0.122 AC: 557 AN: 4574

European-Finnish (FIN) AF: 0.144 AC: 1241 AN: 8596

Middle Eastern (MID) AF: 0.0693 AC: 19 AN: 274

European-Non Finnish (NFE) AF: 0.145 AC: 9492 AN: 65330

Other (OTH) AF: 0.136 AC: 267 AN: 1966

Alfa AF: 0.0452 Hom.: 49

Bravo AF: 0.128

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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		2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34926621; hg19: chr16-46693621;