chr17-532865-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001128159.3(VPS53):c.2062A>G(p.Ile688Val) variant causes a missense change. The variant allele was found at a frequency of 0.00184 in 1,614,096 control chromosomes in the GnomAD database, including 20 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 0.0018 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 17 hom. )

Consequence

VPS53
NM_001128159.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 3.90

Publications

5 publications found

Variant links:

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 2E
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
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

VPS53 links:

ENSG00000263300 (HGNC:58554):

ENSG00000263300 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009616137).

BP6

Variant 17-532865-T-C is Benign according to our data. Variant chr17-532865-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00183 (278/152314) while in subpopulation SAS AF = 0.0137 (66/4828). AF 95% confidence interval is 0.011. There are 3 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS53	NM_001128159.3 link	c.2062A>G	p.Ile688Val	missense_variant	Exon 19 of 22	ENST00000437048.7	NP_001121631.1	Q5VIR6-4B3KS06

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS53	ENST00000437048.7 link	c.2062A>G	p.Ile688Val	missense_variant	Exon 19 of 22	1	NM_001128159.3	ENSP00000401435.2		Q5VIR6-4

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00674

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00338

AC:

842

AN:

248750

AF XY:

0.00378

show subpopulations

Gnomad AFR exome

AF:

0.000432

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00870

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00425

GnomAD4 exome

AF:

0.00184

AC:

2686

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

1543

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.00293

AC:

131

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00390

AC:

102

AN:

26130

East Asian (EAS)

AF:

0.00501

AC:

199

AN:

39700

South Asian (SAS)

AF:

0.0108

AC:

931

AN:

86220

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000975

AC:

1084

AN:

1111968

Other (OTH)

AF:

0.00265

AC:

160

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

138

276

415

553

691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152314

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000409

AC:

AN:

41572

American (AMR)

AF:

0.00327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00675

AC:

AN:

5184

South Asian (SAS)

AF:

0.0137

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00178

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Oct 31, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VPS53: BS1, BS2 -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Microcephaly

Uncertain:1

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Pontocerebellar hypoplasia type 2E

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

.;.;T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

0.014

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;L;.

PhyloP100

3.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.37

N;N;.;N

REVEL

Benign

0.036

Sift

Benign

0.44

T;T;.;T

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.0040

B;B;B;B

Vest4

0.34

MVP

0.23

MPC

0.29

ClinPred

0.0061

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.27

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over