16-46663014-T-C

Variant names:

• chr16-46663014-T-C
• rs1434487321
• NM_018206.6:c.1796A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H599D) has been classified as Uncertain significance.

• 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
• Publications: 12 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), Ambry Genetics, Genomics England PanelApp
• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS35	NM_018206.6	c.1796A>G	p.His599Arg	missense_variant	Exon 14 of 17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.1709A>G	p.His570Arg	missense_variant	Exon 14 of 17		XP_011521529.1
VPS35	XM_005256045.4	c.1595A>G	p.His532Arg	missense_variant	Exon 12 of 15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.1796A>G	p.His599Arg	missense_variant	Exon 14 of 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

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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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
PhyloP100		7.8
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
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs1434487321; hg19: chr16-46696926;