17-519231-G-T

Variant names:

• chr17-519231-G-T
• rs573812629
• NM_001128159.3:c.2396C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001128159.3(VPS53):​c.2396C>A​(p.Ser799*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S799S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS53 NM_001128159.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.39
• Publications: 0 publications found

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 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• progressive cerebello-cerebral atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0412 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128159.3. 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
	VPS53	NM_001128159.3	MANE Select	c.2396C>A	p.Ser799*	stop_gained	Exon 22 of 22	NP_001121631.1	Q5VIR6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000437048.7	TSL:1 MANE Select	c.2396C>A	p.Ser799*	stop_gained	Exon 22 of 22	ENSP00000401435.2	Q5VIR6-4
	VPS53	ENST00000541903.7	TSL:1	n.382C>A		non_coding_transcript_exon	Exon 4 of 4
	VPS53	ENST00000681510.1		c.2246C>A	p.Ser749*	stop_gained	Exon 19 of 19	ENSP00000505594.1	A0A7P0T9B2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.4
Vest4		0.069
GERP RS		5.7

Splicing

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

Other links and lift over

dbSNP: rs573812629; hg19: chr17-422471;