rs144334723

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020964.3(EPG5):c.2998A>G(p.Met1000Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,614,240 control chromosomes in the GnomAD database, including 5 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 0.0023 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 3 hom. )

Consequence

EPG5
NM_020964.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.269

Publications

0 publications found

Variant links:

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

EPG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0045924187).

BP6

Variant 18-45922441-T-C is Benign according to our data. Variant chr18-45922441-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 534607.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00232 (354/152350) while in subpopulation AFR AF = 0.00818 (340/41584). AF 95% confidence interval is 0.00746. There are 2 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3 link	c.2998A>G	p.Met1000Val	missense_variant	Exon 16 of 44	ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11 link	c.2998A>G	p.Met1000Val	missense_variant	Exon 16 of 44	1	NM_020964.3	ENSP00000282041.4

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00818

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000557

AC:

139

AN:

249570

AF XY:

0.000369

show subpopulations

Gnomad AFR exome

AF:

0.00839

Gnomad AMR exome

AF:

0.0000869

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:

0.000825

GnomAD4 exome

AF:

0.000289

AC:

423

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0103

AC:

344

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112010

Other (OTH)

AF:

0.000861

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00232

AC:

354

AN:

152350

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00818

AC:

340

AN:

41584

American (AMR)

AF:

0.000588

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00278

ESP6500AA

AF:

0.00600

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000562

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vici syndrome

Uncertain:2Benign: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 16 p.Met1000Val (c.2998A>G): This variant has not been reported in the literature but is present in 0.8% (190/24024) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs144334723). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 10, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 24, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 12, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

EPG5-related disorder

Benign:1

Jul 25, 2019

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

Jun 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Benign:1

Feb 11, 2020

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0064

T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.65

.;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L

PhyloP100

0.27

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.10

Sift

Benign

0.17

T;.

Sift4G

Benign

0.066

T;.

Polyphen

0.0010

B;B

Vest4

0.19

MVP

0.18

MPC

0.33

ClinPred

0.011

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.42

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over