16-46661719-G-C

Variant names:

• chr16-46661719-G-C
• rs749516404
• NM_018206.6:c.2210C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A737V) has been classified as Uncertain significance.

• 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
• Publications: 4 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

ENSG00000261131 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19865969).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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
PhyloP100		6.7
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

Other links and lift over

dbSNP: rs749516404; hg19: chr16-46695631;