rs1434487321

Positions:

• chr16-46663014-T-C

Variant summary

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

The NM_018206.6(VPS35):​c.1796A>G​(p.His599Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS35 NM_018206.6 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.79

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	Protein	UniProt
VPS35	NM_018206.6	c.1796A>G	p.His599Arg	missense_variant	14/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.1709A>G	p.His570Arg	missense_variant	14/17		XP_011521529.1
VPS35	XM_005256045.4	c.1595A>G	p.His532Arg	missense_variant	12/15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.1796A>G	p.His599Arg	missense_variant	14/17	1	NM_018206.6	ENSP00000299138.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Parkinson disease 17 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.035
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.43
Sift	Benign	0.13	T
Sift4G	Benign	0.37	T
Polyphen		0.10	B
Vest4		0.73
MutPred		0.55		Gain of phosphorylation at T601 (P = 0.0744);
MVP		0.65
MPC		0.61
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1434487321; hg19: chr16-46696926;