rs870181

Variant names:

• chr17-697017-C-T
• rs870181
• NM_001128159.3:c.285+401G>A

Variant summary

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

The NM_001128159.3(VPS53):​c.285+401G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,048 control chromosomes in the GnomAD database, including 4,016 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 0.22 (4016 hom., cov: 31)
• Consequence: VPS53 NM_001128159.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 10 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	NM_001128159.3	MANE Select	c.285+401G>A		intron	N/A	NP_001121631.1
	VPS53	NM_001366253.2		c.285+401G>A		intron	N/A	NP_001353182.1
	VPS53	NM_018289.4		c.285+401G>A		intron	N/A	NP_060759.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000437048.7	TSL:1 MANE Select	c.285+401G>A		intron	N/A	ENSP00000401435.2
	VPS53	ENST00000571805.6	TSL:1	c.285+401G>A		intron	N/A	ENSP00000459312.1
	VPS53	ENST00000291074.10	TSL:1	c.285+401G>A		intron	N/A	ENSP00000291074.5

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33664 AN: 151932 Hom.: 4019 Cov.: 31

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.252

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.0947

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.221 AC: 33645 AN: 152048 Hom.: 4016 Cov.: 31 AF XY: 0.217 AC XY: 16151 AN XY: 74318

African (AFR) AF: 0.144 AC: 5969 AN: 41468

American (AMR) AF: 0.252 AC: 3845 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3470

East Asian (EAS) AF: 0.0949 AC: 490 AN: 5164

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4814

European-Finnish (FIN) AF: 0.183 AC: 1941 AN: 10578

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.264 AC: 17972 AN: 67968

Other (OTH) AF: 0.224 AC: 473 AN: 2116

Alfa AF: 0.259 Hom.: 3123

Bravo AF: 0.220

Asia WGS AF: 0.165 AC: 576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.9
DANN	Benign	0.61
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs870181; hg19: chr17-600257;