17-714860-C-T

Variant names:

• chr17-714860-C-T
• rs2955626
• ENST00000679865.1:c.-151G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000679865.1(VPS53):​c.-151G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000155 in 644,470 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.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: VPS53 ENST00000679865.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.214
• Publications: 14 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000679865.1. 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
	VPS53	NM_001128159.3	MANE Select	c.-151G>A		upstream_gene	N/A	NP_001121631.1	Q5VIR6-4
	VPS53	NM_001366253.2		c.-151G>A		upstream_gene	N/A	NP_001353182.1	Q5VIR6-1
	VPS53	NM_018289.4		c.-151G>A		upstream_gene	N/A	NP_060759.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS53	ENST00000679865.1		c.-151G>A		5_prime_UTR	Exon 1 of 3	ENSP00000504898.1	A0A7P0T804
	VPS53	ENST00000680704.1		c.-282-4247G>A		intron	N/A	ENSP00000506453.1	A0A7P0Z4K0
	VPS53	ENST00000437048.7	TSL:1 MANE Select	c.-151G>A		upstream_gene	N/A	ENSP00000401435.2	Q5VIR6-4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000155 AC: 1 AN: 644470 Hom.: 0 Cov.: 8 AF XY: 0.00000293 AC XY: 1 AN XY: 340834

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17246

American (AMR) AF: 0.00 AC: 0 AN: 31076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17076

East Asian (EAS) AF: 0.00 AC: 0 AN: 33008

South Asian (SAS) AF: 0.00 AC: 0 AN: 60530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2744

European-Non Finnish (NFE) AF: 0.00000241 AC: 1 AN: 414386

Other (OTH) AF: 0.00 AC: 0 AN: 33018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.96
PhyloP100		-0.21
PromoterAI		0.054	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2955626; hg19: chr17-618100;