17-714860-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000679865.1(VPS53):​c.-151G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 795,868 control chromosomes in the GnomAD database, including 123,693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (29150 hom., cov: 34)
  • Exomes 𝑓: 0.53 (94543 hom.)
• Consequence: VPS53 ENST00000679865.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 17-714860-C-G is Benign according to our data. Variant chr17-714860-C-G is described in ClinVar as Benign. ClinVar VariationId is 1231609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS53	NM_001128159.3	c.-151G>C		upstream_gene_variant		ENST00000437048.7	NP_001121631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS53	ENST00000437048.7	c.-151G>C		upstream_gene_variant		1	NM_001128159.3	ENSP00000401435.2

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91267 AN: 152072 Hom.: 29116 Cov.: 34

Gnomad AFR AF: 0.801

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.867

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.591

GnomAD4 exome AF: 0.535 AC: 344072 AN: 643678 Hom.: 94543 Cov.: 8 AF XY: 0.531 AC XY: 180778 AN XY: 340418

African (AFR) AF: 0.811 AC: 13988 AN: 17240

American (AMR) AF: 0.633 AC: 19660 AN: 31048

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 8046 AN: 17054

East Asian (EAS) AF: 0.843 AC: 27796 AN: 32992

South Asian (SAS) AF: 0.526 AC: 31821 AN: 60488

European-Finnish (FIN) AF: 0.553 AC: 19552 AN: 35360

Middle Eastern (MID) AF: 0.575 AC: 1574 AN: 2738

European-Non Finnish (NFE) AF: 0.492 AC: 203501 AN: 413768

Other (OTH) AF: 0.550 AC: 18134 AN: 32990

GnomAD4 genome AF: 0.600 AC: 91355 AN: 152190 Hom.: 29150 Cov.: 34 AF XY: 0.602 AC XY: 44783 AN XY: 74418

African (AFR) AF: 0.801 AC: 33275 AN: 41538

American (AMR) AF: 0.593 AC: 9080 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 1597 AN: 3472

East Asian (EAS) AF: 0.866 AC: 4483 AN: 5174

South Asian (SAS) AF: 0.508 AC: 2456 AN: 4830

European-Finnish (FIN) AF: 0.556 AC: 5894 AN: 10600

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.483 AC: 32826 AN: 67960

Other (OTH) AF: 0.595 AC: 1257 AN: 2112

Alfa AF: 0.547 Hom.: 2965

Bravo AF: 0.615

Asia WGS AF: 0.667 AC: 2319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.94
PhyloP100		-0.21
PromoterAI		0.068	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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;