rs192783364

Positions:

• chr16-46677396-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_018206.6(VPS35):​c.723T>G​(p.Ile241Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS35 NM_018206.6 missense, splice_region
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.95

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VPS35. . Gene score misZ 3.5321 (greater than the threshold 3.09). Trascript score misZ 4.8931 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, hereditary late onset Parkinson disease, Parkinson disease, Parkinson disease 17.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37549585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.723T>G	p.Ile241Met	missense_variant, splice_region_variant	7/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.636T>G	p.Ile212Met	missense_variant, splice_region_variant	7/17		XP_011521529.1
VPS35	XM_005256045.4	c.522T>G	p.Ile174Met	missense_variant, splice_region_variant	5/15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.723T>G	p.Ile241Met	missense_variant, splice_region_variant	7/17	1	NM_018206.6	ENSP00000299138.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	Benign	0.068
BayesDel_addAF	Benign	-0.0040	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Polyphen		0.95	P
Vest4		0.58
MutPred		0.32		Loss of catalytic residue at I241 (P = 0.065);
MVP		0.38
MPC		1.6
ClinPred		0.42	T
GERP RS		0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs192783364; hg19: chr16-46711308;