NM_020964.3:c.1696A>G

Variant names:

• chr18-45944101-T-C
• rs767119998
• NM_020964.3:c.1696A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020964.3(EPG5):​c.1696A>G​(p.Ser566Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.97
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33561677).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020964.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	NM_020964.3	MANE Select	c.1696A>G	p.Ser566Gly	missense	Exon 8 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.1696A>G	p.Ser566Gly	missense	Exon 8 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.1696A>G	p.Ser566Gly	missense	Exon 8 of 44	NP_001397787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.1696A>G	p.Ser566Gly	missense	Exon 8 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.1696A>G		non_coding_transcript_exon	Exon 8 of 45	ENSP00000466990.2
	EPG5	ENST00000587974.1	TSL:1	n.1731A>G		non_coding_transcript_exon	Exon 8 of 24

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000281 AC: 7 AN: 249506 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460390 Hom.: 0 Cov.: 29 AF XY: 0.00000688 AC XY: 5 AN XY: 726644

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.000201 AC: 9 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110722

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vici syndrome Uncertain:2

Apr 26, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 566 of the EPG5 protein (p.Ser566Gly). This variant is present in population databases (rs767119998, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with EPG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 582488). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EPG5 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.20
MutPred		0.27		Loss of phosphorylation at S566 (P = 0.0669)
MVP		0.63
MPC		0.56
ClinPred		0.39	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.40
Mutation Taster		=65/35	polymorphism

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: rs767119998; hg19: chr18-43524067;