17-519155-G-C

Variant names:

• chr17-519155-G-C
• rs376440772
• NM_001128159.3:c.2472C>G

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.2472C>G​(p.Leu824Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,386,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L824L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: VPS53 NM_001128159.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• 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=-0.87).
• BP7: Synonymous conserved (PhyloP=-2.32 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.2472C>G	p.Leu824Leu	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.2472C>G	p.Leu824Leu	synonymous	Exon 22 of 22	ENSP00000401435.2	Q5VIR6-4
	VPS53	ENST00000541903.7	TSL:1	n.458C>G		non_coding_transcript_exon	Exon 4 of 4
	VPS53	ENST00000681510.1		c.2322C>G	p.Leu774Leu	synonymous	Exon 19 of 19	ENSP00000505594.1	A0A7P0T9B2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1386858 Hom.: 0 Cov.: 30 AF XY: 0.00000439 AC XY: 3 AN XY: 683792

African (AFR) AF: 0.00 AC: 0 AN: 30800

American (AMR) AF: 0.00 AC: 0 AN: 32378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24476

East Asian (EAS) AF: 0.00 AC: 0 AN: 35476

South Asian (SAS) AF: 0.00 AC: 0 AN: 77680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000466 AC: 5 AN: 1074036

Other (OTH) AF: 0.00 AC: 0 AN: 57376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.023
DANN	Benign	0.62
PhyloP100		-2.3

Splicing

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

Other links and lift over

dbSNP: rs376440772; hg19: chr17-422395;