18-45855635-T-C

Variant names:

• chr18-45855635-T-C
• rs191244915
• NM_020964.3:c.7495A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020964.3(EPG5):​c.7495A>G​(p.Met2499Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,614,166 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (3 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.951
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003611356).
• BP6: Variant 18-45855635-T-C is Benign according to our data. Variant chr18-45855635-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534604.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00152 (231/152288) while in subpopulation AFR AF = 0.00525 (218/41548). AF 95% confidence interval is 0.00468. There are 0 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.7495A>G	p.Met2499Val	missense	Exon 43 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.7492A>G	p.Met2498Val	missense	Exon 43 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.7495A>G	p.Met2499Val	missense	Exon 43 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.7495A>G	p.Met2499Val	missense	Exon 43 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.*3235A>G		non_coding_transcript_exon	Exon 44 of 45	ENSP00000466990.2
	EPG5	ENST00000590884.6	TSL:1	n.*1807A>G		non_coding_transcript_exon	Exon 41 of 42	ENSP00000466403.2

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000373 AC: 93 AN: 249382 AF XY: 0.000281

Gnomad AFR exome AF: 0.00433

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1461878 Hom.: 3 Cov.: 30 AF XY: 0.000142 AC XY: 103 AN XY: 727240

African (AFR) AF: 0.00454 AC: 152 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1112004

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74464

African (AFR) AF: 0.00525 AC: 218 AN: 41548

American (AMR) AF: 0.000523 AC: 8 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000658 Hom.: 0

Bravo AF: 0.00157

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00366 AC: 14

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000455 AC: 55

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Vici syndrome Uncertain:1 Benign:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EPG5: NM_020964 exon 64 p.Met2499Val (c.7495A>G): This variant has not been reported in the literature but is present in 0.4% (115/24016) of African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs191244915). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EPG5-related disorder Benign:1

May 25, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Oct 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Limb-girdle muscular dystrophy Benign:1

Aug 28, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.96
DANN	Benign	0.60
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.95
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.010
Sift	Benign	0.26	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.15
MPC		0.15
ClinPred		0.0040	T
GERP RS		-5.9
Varity_R		0.049
gMVP		0.14
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs191244915; hg19: chr18-43435600; COSMIC: COSV99956218; COSMIC: COSV99956218;