6-33267976-C-T

Variant names:

• chr6-33267976-C-T
• rs755294872
• NM_022553.6:c.822G>A
• VPS52 p.Leu274Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022553.6(VPS52):​c.822G>A​(p.Leu274Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: VPS52 NM_022553.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022553.6. 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
	VPS52	NM_022553.6	MANE Select	c.822G>A	p.Leu274Leu	synonymous	Exon 9 of 20	NP_072047.4
	VPS52	NM_001289174.2		c.621G>A	p.Leu207Leu	synonymous	Exon 8 of 19	NP_001276103.1
	VPS52	NM_001289175.1		c.447G>A	p.Leu149Leu	synonymous	Exon 9 of 20	NP_001276104.1	Q8N1B4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS52	ENST00000445902.3	TSL:1 MANE Select	c.822G>A	p.Leu274Leu	synonymous	Exon 9 of 20	ENSP00000409952.2	Q8N1B4-1
	VPS52	ENST00000865494.1		c.903G>A	p.Leu301Leu	synonymous	Exon 9 of 20	ENSP00000535553.1
	VPS52	ENST00000954722.1		c.822G>A	p.Leu274Leu	synonymous	Exon 10 of 21	ENSP00000624781.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 246762 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460798 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726712

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.82
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 8

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: rs755294872;

hg19: chr6-33235753;