Variant 6-33264879-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022553.6(VPS52):c.1303G>A(p.Ala435Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS52
NM_022553.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0560

Variant links:

Genes affected

VPS52 (HGNC:10518): (VPS52 subunit of GARP complex) This gene encodes a protein that is similar to the yeast suppressor of actin mutations 2 gene. The yeast protein forms a subunit of the tetrameric Golgi-associated retrograde protein complex that is involved in vesicle trafficking from from both early and late endosomes, back to the trans-Golgi network. This gene is located on chromosome 6 in a head-to-head orientation with the gene encoding ribosomal protein S18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

VPS52 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049981207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS52	NM_022553.6 linkuse as main transcript	c.1303G>A	p.Ala435Thr	missense_variant	13/20	ENST00000445902.3	NP_072047.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS52	ENST00000445902.3 linkuse as main transcript	c.1303G>A	p.Ala435Thr	missense_variant	13/20	1	NM_022553.6	ENSP00000409952	P1	Q8N1B4-1
VPS52	ENST00000482399.5 linkuse as main transcript	c.*1432G>A		3_prime_UTR_variant	12/19	2		ENSP00000436612
VPS52	ENST00000478934.5 linkuse as main transcript	n.1164G>A		non_coding_transcript_exon_variant	11/18	2
VPS52	ENST00000493379.1 linkuse as main transcript	n.256G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460714

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.1303G>A (p.A435T) alteration is located in exon 13 (coding exon 13) of the VPS52 gene. This alteration results from a G to A substitution at nucleotide position 1303, causing the alanine (A) at amino acid position 435 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.8

DANN

Benign

0.94

DEOGEN2

Benign

0.016

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.042

M_CAP

Benign

0.0041

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.20

REVEL

Benign

0.14

Sift

Benign

0.43

Sift4G

Benign

0.49

Polyphen

0.0050

Vest4

0.029

MutPred

0.52

Loss of stability (P = 0.0446);

MVP

0.12

MPC

0.60

ClinPred

0.16

GERP RS

-4.9

Varity_R

0.017

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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