rs59422275

chr18-45954858-T-C

Variant summary

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

The NM_020964.3(EPG5):c.544A>G(p.Lys182Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,614,110 control chromosomes in the GnomAD database, including 7,085 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K182K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5723 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.10

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 (MetaRNN=0.0038298368).
• BP6: Variant 18-45954858-T-C is Benign according to our data. Variant chr18-45954858-T-C is described in ClinVar as [Benign]. Clinvar id is 402834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45954858-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.544A>G	p.Lys182Glu	missense_variant	2/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.544A>G	p.Lys182Glu	missense_variant	2/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17605 AN: 152180 Hom.: 1358 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0778

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0989

GnomAD3 exomes AF: 0.0845 AC: 21063 AN: 249294 Hom.: 1105 AF XY: 0.0833 AC XY: 11274 AN XY: 135272

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0778

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0233

Gnomad SAS exome AF: 0.0871

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0802

Gnomad OTH exome AF: 0.0848

GnomAD4 exome AF: 0.0826 AC: 120703 AN: 1461812 Hom.: 5723 Cov.: 32 AF XY: 0.0825 AC XY: 59982 AN XY: 727210

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.0780

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.0207

Gnomad4 SAS exome AF: 0.0859

Gnomad4 FIN exome AF: 0.0487

Gnomad4 NFE exome AF: 0.0809

Gnomad4 OTH exome AF: 0.0874

GnomAD4 genome AF: 0.116 AC: 17618 AN: 152298 Hom.: 1362 Cov.: 33 AF XY: 0.112 AC XY: 8319 AN XY: 74458

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.0777

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.0236

Gnomad4 SAS AF: 0.0766

Gnomad4 FIN AF: 0.0439

Gnomad4 NFE AF: 0.0835

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.0897 Hom.: 1170

Bravo AF: 0.123

TwinsUK AF: 0.0736 AC: 273

ALSPAC AF: 0.0734 AC: 283

ESP6500AA AF: 0.203 AC: 784

ESP6500EA AF: 0.0832 AC: 687

ExAC AF: 0.0872 AC: 10530

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.0840

EpiControl AF: 0.0848

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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: MAF -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 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. -

Vici syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	7.5
Dann	Benign	0.92
DEOGEN2	Benign	0.0035	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.039
Sift	Benign	0.51	T;.
Sift4G	Benign	0.54	T;.
Polyphen		0.0010	B;B
Vest4		0.065
MPC		0.21
ClinPred		0.0032	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs59422275; hg19: chr18-43534824; COSMIC: COSV56346706;