rs57761448

Positions:

• chr18-45852660-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000282041.11(EPG5):​c.7558-11G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,610,974 control chromosomes in the GnomAD database, including 9,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (884 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8596 hom.)
• Consequence: EPG5 ENST00000282041.11 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005633
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.42

Genes affected

EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-45852660-C-T is Benign according to our data. Variant chr18-45852660-C-T is described in ClinVar as [Benign]. Clinvar id is 402831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45852660-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPG5	NM_020964.3	c.7558-11G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11	c.7558-11G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_020964.3	ENSP00000282041	P4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15886 AN: 152058 Hom.: 886 Cov.: 33

Gnomad AFR AF: 0.0906

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.105 AC: 26107 AN: 247652 Hom.: 1573 AF XY: 0.101 AC XY: 13604 AN XY: 134406

Gnomad AFR exome AF: 0.0888

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.186

Gnomad SAS exome AF: 0.0435

Gnomad FIN exome AF: 0.0989

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.105 AC: 153363 AN: 1458798 Hom.: 8596 Cov.: 31 AF XY: 0.104 AC XY: 75148 AN XY: 725762

Gnomad4 AFR exome AF: 0.0883

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0452

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.104 AC: 15899 AN: 152176 Hom.: 884 Cov.: 33 AF XY: 0.103 AC XY: 7656 AN XY: 74396

Gnomad4 AFR AF: 0.0904

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.0458

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.103

Alfa AF: 0.105 Hom.: 332

Bravo AF: 0.106

Asia WGS AF: 0.0850 AC: 298 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Vici syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.026
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs57761448; hg19: chr18-43432625; COSMIC: COSV56344727; COSMIC: COSV56344727;