rs684232

Variant names:

• chr17-715725-T-C
• rs684232
• ENST00000680704.1:c.-282-5112A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000680704.1(VPS53):​c.-282-5112A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 151,920 control chromosomes in the GnomAD database, including 17,251 homozygotes. 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: 𝑓 0.45 (17251 hom., cov: 31)
• Consequence: VPS53 ENST00000680704.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0240
• Publications: 70 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 2E

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000680704.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000680704.1		c.-282-5112A>G		intron	N/A	ENSP00000506453.1	A0A7P0Z4K0

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68953 AN: 151802 Hom.: 17216 Cov.: 31

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.444

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.454 AC: 69044 AN: 151920 Hom.: 17251 Cov.: 31 AF XY: 0.452 AC XY: 33582 AN XY: 74254

African (AFR) AF: 0.659 AC: 27278 AN: 41376

American (AMR) AF: 0.428 AC: 6533 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 992 AN: 3464

East Asian (EAS) AF: 0.576 AC: 2972 AN: 5164

South Asian (SAS) AF: 0.428 AC: 2057 AN: 4804

European-Finnish (FIN) AF: 0.327 AC: 3451 AN: 10550

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.360 AC: 24480 AN: 67980

Other (OTH) AF: 0.449 AC: 941 AN: 2098

Alfa AF: 0.395 Hom.: 37784

Bravo AF: 0.468

Asia WGS AF: 0.522 AC: 1814 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.9
DANN	Benign	0.49
PhyloP100		-0.024
PromoterAI		-0.26	Neutral

Splicing

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

Other links and lift over

dbSNP: rs684232; hg19: chr17-618965;