16-46661719-G-C

Position:

• chr16-46661719-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018206.6(VPS35):​c.2210C>G​(p.Ala737Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS35 NM_018206.6 missense, splice_region
• Scores: Splicing: ADA: 0.9591
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.72

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 1 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=0.19865969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.2210C>G	p.Ala737Gly	missense_variant, splice_region_variant	16/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.2123C>G	p.Ala708Gly	missense_variant, splice_region_variant	16/17		XP_011521529.1
VPS35	XM_005256045.4	c.2009C>G	p.Ala670Gly	missense_variant, splice_region_variant	14/15		XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.2210C>G	p.Ala737Gly	missense_variant, splice_region_variant	16/17	1	NM_018206.6	ENSP00000299138.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.056
Sift	Benign	0.19	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.43		Loss of stability (P = 0.0442);
MVP		0.20
MPC		0.48
ClinPred		0.69	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.69
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: rs749516404; hg19: chr16-46695631;