rs587777465

chr17-532843-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001128159.3(VPS53):c.2084A>G(p.Gln695Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS53 NM_001128159.3 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57

Genes affected

VPS53 (HGNC:25608): (VPS53 subunit of GARP complex) Involved in endocytic recycling and retrograde transport, endosome to Golgi. Acts upstream of or within lysosomal transport. Located in several cellular components, including Golgi apparatus; perinuclear region of cytoplasm; and recycling endosome. Part of EARP complex and GARP complex. Implicated in pontocerebellar hypoplasia type 2E. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893
• PP5: Variant 17-532843-T-C is Pathogenic according to our data. Variant chr17-532843-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 139444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-532843-T-C is described in UniProt as null. Variant chr17-532843-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS53	NM_001128159.3	c.2084A>G	p.Gln695Arg	missense_variant, splice_region_variant	19/22	ENST00000437048.7
LOC124903890	XR_007065570.1	n.694-7546T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS53	ENST00000437048.7	c.2084A>G	p.Gln695Arg	missense_variant, splice_region_variant	19/22	1	NM_001128159.3	P1
	ENST00000570974.1	n.291-7546T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 2E Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 22, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 695 of the VPS53 protein (p.Gln695Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with progressive cerebello-cerebral atrophy type 2 and/or spastic paraparesis, developmental delay, and epileptic features (PMID: 24577744, 30100179, 31418091). It is commonly reported in individuals of Moroccan Jewish ancestry (PMID: 24577744, 30100179, 31418091). ClinVar contains an entry for this variant (Variation ID: 139444). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects VPS53 function (PMID: 26357016). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.5	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D;D;.;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.95
MutPred		0.65		Gain of MoRF binding (P = 0.0148);.;Gain of MoRF binding (P = 0.0148);.;
MVP		0.73
MPC		1.1
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.93

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: rs587777465; hg19: chr17-436083;