chr18-45865765-CA-C

Position:

• chr18-45865765-CA-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000282041.11(EPG5):​c.6622-7del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 102,434 control chromosomes in the GnomAD database, including 1,636 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (1636 hom., cov: 25)
  • Exomes 𝑓: 0.33 (184 hom.)
  • Failed GnomAD Quality Control
• Consequence: EPG5 ENST00000282041.11 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.327

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 -16 ACMG points.

• BP6: Variant 18-45865765-CA-C is Benign according to our data. Variant chr18-45865765-CA-C is described in ClinVar as [Benign]. Clinvar id is 402832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45865765-CA-C is described in Lovd as [Benign]. Variant chr18-45865765-CA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPG5	NM_020964.3	c.6622-7del		splice_region_variant, 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.6622-7del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020964.3	ENSP00000282041	P4

Frequencies

GnomAD3 genomes AF: 0.193 AC: 19781 AN: 102424 Hom.: 1634 Cov.: 25

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0983

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.198

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.329 AC: 378011 AN: 1150714 Hom.: 184 Cov.: 0 AF XY: 0.328 AC XY: 186861 AN XY: 569160

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.358

Gnomad4 ASJ exome AF: 0.343

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.340

GnomAD4 genome AF: 0.193 AC: 19779 AN: 102434 Hom.: 1636 Cov.: 25 AF XY: 0.205 AC XY: 10072 AN XY: 49228

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.198

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 - No homozygotes in ExAC -
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 39% of patients studied by a panel of primary immunodeficiencies. Number of patients: 37. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Vici syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 12, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs11333207; hg19: chr18-43445730;