18-45917745-A-G

Variant names:

• chr18-45917745-A-G
• rs3744998
• NM_020964.3:c.3173T>C

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.3173T>C​(p.Val1058Ala) variant causes a missense change. The variant allele was found at a frequency of 0.53 in 1,613,394 control chromosomes in the GnomAD database, including 231,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1058L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (17729 hom., cov: 32)
  • Exomes 𝑓: 0.54 (213706 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 6.65
• Publications: 40 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 (MetaRNN=3.9723516E-4).
• BP6: Variant 18-45917745-A-G is Benign according to our data. Variant chr18-45917745-A-G is described in ClinVar as Benign. ClinVar VariationId is 402833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3	c.3173T>C	p.Val1058Ala	missense_variant	Exon 17 of 44	ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11	c.3173T>C	p.Val1058Ala	missense_variant	Exon 17 of 44	1	NM_020964.3	ENSP00000282041.4

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71123 AN: 151958 Hom.: 17724 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.493

GnomAD2 exomes AF: 0.490 AC: 122181 AN: 249322 AF XY: 0.494

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.339

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.583

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.494

GnomAD4 exome AF: 0.536 AC: 783929 AN: 1461318 Hom.: 213706 Cov.: 41 AF XY: 0.534 AC XY: 388019 AN XY: 726990

African (AFR) AF: 0.310 AC: 10375 AN: 33468

American (AMR) AF: 0.347 AC: 15487 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 13933 AN: 26130

East Asian (EAS) AF: 0.561 AC: 22240 AN: 39668

South Asian (SAS) AF: 0.397 AC: 34243 AN: 86212

European-Finnish (FIN) AF: 0.537 AC: 28673 AN: 53414

Middle Eastern (MID) AF: 0.476 AC: 2744 AN: 5764

European-Non Finnish (NFE) AF: 0.562 AC: 624610 AN: 1111608

Other (OTH) AF: 0.524 AC: 31624 AN: 60366

GnomAD4 genome AF: 0.468 AC: 71153 AN: 152076 Hom.: 17729 Cov.: 32 AF XY: 0.466 AC XY: 34610 AN XY: 74326

African (AFR) AF: 0.304 AC: 12601 AN: 41472

American (AMR) AF: 0.415 AC: 6343 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1887 AN: 3468

East Asian (EAS) AF: 0.582 AC: 3011 AN: 5176

South Asian (SAS) AF: 0.396 AC: 1911 AN: 4828

European-Finnish (FIN) AF: 0.529 AC: 5586 AN: 10560

Middle Eastern (MID) AF: 0.459 AC: 134 AN: 292

European-Non Finnish (NFE) AF: 0.559 AC: 37965 AN: 67974

Other (OTH) AF: 0.493 AC: 1042 AN: 2112

Alfa AF: 0.530 Hom.: 103377

Bravo AF: 0.454

TwinsUK AF: 0.559 AC: 2074

ALSPAC AF: 0.568 AC: 2188

ESP6500AA AF: 0.293 AC: 1105

ESP6500EA AF: 0.565 AC: 4654

ExAC AF: 0.490 AC: 59268

Asia WGS AF: 0.444 AC: 1547 AN: 3478

EpiCase AF: 0.557

EpiControl AF: 0.550

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vici syndrome Benign:3

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

Mar 24, 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

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

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 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	.;T
MetaRNN	Benign	0.00040	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		6.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.094
Sift	Uncertain	0.0040	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.88	P;P
Vest4		0.23
MPC		0.66
ClinPred		0.027	T
GERP RS		5.4
Varity_R		0.20
gMVP		0.60
Mutation Taster		=59/41	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3744998; hg19: chr18-43497710; COSMIC: COSV56348892; COSMIC: COSV56348892;