6-33267243-G-C

Position:

• chr6-33267243-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022553.6(VPS52):​c.1070C>G​(p.Thr357Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: VPS52 NM_022553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10957262).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS52	NM_022553.6	c.1070C>G	p.Thr357Ser	missense_variant	11/20	ENST00000445902.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS52	ENST00000445902.3	c.1070C>G	p.Thr357Ser	missense_variant	11/20	1	NM_022553.6	P1
VPS52	ENST00000482399.5	c.*1199C>G		3_prime_UTR_variant	10/19	2
VPS52	ENST00000493379.1	n.23C>G		non_coding_transcript_exon_variant	1/4	5
VPS52	ENST00000478934.5	n.987-531C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.1070C>G (p.T357S) alteration is located in exon 11 (coding exon 11) of the VPS52 gene. This alteration results from a C to G substitution at nucleotide position 1070, causing the threonine (T) at amino acid position 357 to be replaced by a serine (S). 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	0.065
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.037
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N
MutationTaster	Benign	0.74	D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.091
Sift	Benign	0.91	T
Sift4G	Benign	0.78	T
Polyphen		0.0030	B
Vest4		0.19
MutPred		0.29		Gain of disorder (P = 0.0442);
MVP		0.52
MPC		0.52
ClinPred		0.63	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375209798; hg19: chr6-33235020;