17-532865-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 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

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 links:

ENSG00000263300 (HGNC:):

ENSG00000263300 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.00338

AC:

842

AN:

248750

Hom.:

AF XY:

0.00378

AC XY:

509

AN XY:

134660

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 SAS exome

AF:

0.0118

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

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.00390

Gnomad4 EAS exome

AF:

0.00501

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.000975

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152314

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00675

Gnomad4 SAS

AF:

0.0137

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00188

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

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

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VPS53: BS1, BS2 -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over