17-519236-C-G

Variant names:

• chr17-519236-C-G
• NM_001128159.3:c.2391G>C
• VPS53 p.Pro797Pro

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001128159.3(VPS53):​c.2391G>C​(p.Pro797Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. P797P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS53 NM_001128159.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.13
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=-3.13 with no splicing effect.

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.2391G>C	p.Pro797Pro	synonymous	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.2391G>C	p.Pro797Pro	synonymous	Exon 22 of 22	ENSP00000401435.2	Q5VIR6-4
	VPS53	ENST00000541903.7	TSL:1	n.377G>C		non_coding_transcript_exon	Exon 4 of 4
	VPS53	ENST00000681510.1		c.2241G>C	p.Pro747Pro	synonymous	Exon 19 of 19	ENSP00000505594.1	A0A7P0T9B2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.093
DANN	Benign	0.59
PhyloP100		-3.1

Splicing

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

hg19: chr17-422476;