16-46660184-G-GGTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018206.6(VPS35):c.*287_*288insAAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS35	NM_018206.6	c.*287_*288insAAC		3_prime_UTR_variant	17/17	ENST00000299138.12
VPS35	XM_005256045.4	c.*287_*288insAAC		3_prime_UTR_variant	15/15
VPS35	XM_011523227.4	c.*287_*288insAAC		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS35	ENST00000299138.12	c.*287_*288insAAC		3_prime_UTR_variant	17/17	1	NM_018206.6	P1
VPS35	ENST00000568784.6	c.*3348_*3349insAAC		3_prime_UTR_variant, NMD_transcript_variant	17/17	1
VPS35	ENST00000647959.1	c.*2741_*2742insAAC		3_prime_UTR_variant, NMD_transcript_variant	18/18

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson Disease, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555522760; hg19: chr16-46694096;