16-46682127-C-T

Position:

• chr16-46682127-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_018206.6(VPS35):​c.151G>A​(p.Gly51Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,488 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: VPS35 NM_018206.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 7.91

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 Benign. Variant got -15 ACMG points.

• 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=0.033385128).
• BP6: Variant 16-46682127-C-T is Benign according to our data. Variant chr16-46682127-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 487668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.151G>A	p.Gly51Ser	missense_variant	3/17	ENST00000299138.12	NP_060676.2
VPS35	XM_011523227.4	c.64G>A	p.Gly22Ser	missense_variant	3/17		XP_011521529.1
VPS35	XM_005256045.4	c.-22-607G>A		intron_variant			XP_005256102.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.151G>A	p.Gly51Ser	missense_variant	3/17	1	NM_018206.6	ENSP00000299138.7

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000454 AC: 114 AN: 251040 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000222 AC: 325 AN: 1461276 Hom.: 1 Cov.: 30 AF XY: 0.000226 AC XY: 164 AN XY: 726954

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.000581

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.0000693

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2020	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Parkinson disease 17 Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.65
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.25
Eigen_PC	Benign	0.0057
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.43	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.027	B
Vest4		0.70
MVP		0.57
MPC		0.53
ClinPred		0.74	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.53
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs193077277; hg19: chr16-46716039;