rs57761448

Variant names:

• chr18-45852660-C-T
• rs57761448
• NM_020964.3:c.7558-11G>A

Variant summary

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

The NM_020964.3(EPG5):​c.7558-11G>A variant causes a 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 NM_020964.3 intron
• Scores: Splicing: ADA: 0.00005633
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.42
• Publications: 5 publications found

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]

EPG5 Gene-Disease associations (from GenCC):

• Vici syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 402831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3	c.7558-11G>A		intron_variant	Intron 43 of 43	ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11	c.7558-11G>A		intron_variant	Intron 43 of 43	1	NM_020964.3	ENSP00000282041.4

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

GnomAD2 exomes AF: 0.105 AC: 26107 AN: 247652 AF XY: 0.101

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 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

African (AFR) AF: 0.0883 AC: 2947 AN: 33382

American (AMR) AF: 0.109 AC: 4850 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3607 AN: 25974

East Asian (EAS) AF: 0.147 AC: 5816 AN: 39676

South Asian (SAS) AF: 0.0452 AC: 3892 AN: 86048

European-Finnish (FIN) AF: 0.103 AC: 5467 AN: 53254

Middle Eastern (MID) AF: 0.0627 AC: 361 AN: 5756

European-Non Finnish (NFE) AF: 0.108 AC: 120142 AN: 1109908

Other (OTH) AF: 0.104 AC: 6281 AN: 60270

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

African (AFR) AF: 0.0904 AC: 3752 AN: 41518

American (AMR) AF: 0.114 AC: 1741 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3472

East Asian (EAS) AF: 0.169 AC: 873 AN: 5168

South Asian (SAS) AF: 0.0458 AC: 221 AN: 4822

European-Finnish (FIN) AF: 0.102 AC: 1082 AN: 10598

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7391 AN: 68000

Other (OTH) AF: 0.103 AC: 218 AN: 2112

Alfa AF: 0.108 Hom.: 1553

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

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Apr 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Vici syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.83
CADD	Benign	0.026
DANN	Benign	0.40
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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