ENST00000680704.1:c.-282-5309T>C

Variant names:

• chr17-715922-A-G
• rs461251
• ENST00000680704.1:c.-282-5309T>C

Variant summary

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

The ENST00000680704.1(VPS53):​c.-282-5309T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 151,808 control chromosomes in the GnomAD database, including 18,923 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 0.48 (18923 hom., cov: 31)
• Consequence: VPS53 ENST00000680704.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0410
• Publications: 17 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=-0.69).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.675 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000680704.1		c.-282-5309T>C		intron	N/A	ENSP00000506453.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72701 AN: 151690 Hom.: 18888 Cov.: 31

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.479 AC: 72790 AN: 151808 Hom.: 18923 Cov.: 31 AF XY: 0.477 AC XY: 35401 AN XY: 74178

African (AFR) AF: 0.682 AC: 28231 AN: 41406

American (AMR) AF: 0.448 AC: 6819 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1158 AN: 3466

East Asian (EAS) AF: 0.602 AC: 3078 AN: 5110

South Asian (SAS) AF: 0.464 AC: 2229 AN: 4808

European-Finnish (FIN) AF: 0.351 AC: 3695 AN: 10524

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26231 AN: 67950

Other (OTH) AF: 0.464 AC: 975 AN: 2102

Alfa AF: 0.416 Hom.: 13881

Bravo AF: 0.492

Asia WGS AF: 0.549 AC: 1908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		-0.041

Splicing

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

Other links and lift over

dbSNP: rs461251; hg19: chr17-619162;