ENST00000571805.6:c.2084A>G

Variant names:

• chr17-532843-T-C
• rs587777465
• ENST00000571805.6:c.2084A>G
• VPS53 p.Gln695Arg

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000571805.6(VPS53):​c.2084A>G​(p.Gln695Arg) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004296446: Experimental studies have shown that this missense change affects VPS53 function (PMID:26357016).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS53 ENST00000571805.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.57
• Publications: 6 publications found

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]

VPS53 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• progressive cerebello-cerebral atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000263300 (HGNC:58554):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004296446: Experimental studies have shown that this missense change affects VPS53 function (PMID: 26357016).
• 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 VariationId is 139444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000571805.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	NM_001128159.3	MANE Select	c.2084A>G	p.Gln695Arg	missense splice_region	Exon 19 of 22	NP_001121631.1	Q5VIR6-4
	VPS53	NM_001366253.2		c.2084A>G	p.Gln695Arg	missense	Exon 19 of 19	NP_001353182.1	Q5VIR6-1
	VPS53	NM_018289.4		c.1997A>G	p.Gln666Arg	missense	Exon 18 of 18	NP_060759.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000571805.6	TSL:1	c.2084A>G	p.Gln695Arg	missense	Exon 19 of 19	ENSP00000459312.1	Q5VIR6-1
	VPS53	ENST00000291074.10	TSL:1	c.1997A>G	p.Gln666Arg	missense	Exon 18 of 18	ENSP00000291074.5	Q5VIR6-2
	VPS53	ENST00000401468.7	TSL:1	c.1253A>G	p.Gln418Arg	missense	Exon 12 of 12	ENSP00000384294.3	E7EVT8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Pontocerebellar hypoplasia type 2E (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.79	D
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
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587777465;

hg19: chr17-436083;