17-519137-C-G

Variant names:

• chr17-519137-C-G
• rs1392629585
• NM_001128159.3:c.2490G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001128159.3(VPS53):​c.2490G>C​(p.Lys830Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,372,990 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K830K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: VPS53 NM_001128159.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.841
• 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 2 ACMG points.

• 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.2490G>C	p.Lys830Asn	missense	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.2490G>C	p.Lys830Asn	missense	Exon 22 of 22	ENSP00000401435.2	Q5VIR6-4
	VPS53	ENST00000541903.7	TSL:1	n.476G>C		non_coding_transcript_exon	Exon 4 of 4
	VPS53	ENST00000681510.1		c.2340G>C	p.Lys780Asn	missense	Exon 19 of 19	ENSP00000505594.1	A0A7P0T9B2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1372990 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 675864

African (AFR) AF: 0.00 AC: 0 AN: 30300

American (AMR) AF: 0.00 AC: 0 AN: 30064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23490

East Asian (EAS) AF: 0.00 AC: 0 AN: 35272

South Asian (SAS) AF: 0.00 AC: 0 AN: 75214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1067756

Other (OTH) AF: 0.00 AC: 0 AN: 56770

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.96
Eigen	Benign	0.077
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.94	T
PhyloP100		0.84
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.57
MutPred		0.18		Loss of methylation at K830 (P = 0.0425)
MVP		0.55
MPC		0.39
ClinPred		0.93	D
GERP RS		2.6
gMVP		0.51
Mutation Taster		=72/28	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1392629585; hg19: chr17-422377;