rs144334723

Positions:

chr18-45922441-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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:5

Conservation

PhyloP100: 0.269

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 534607.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3 linkuse as main transcript	c.2998A>G	p.Met1000Val	missense_variant	16/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11 linkuse as main transcript	c.2998A>G	p.Met1000Val	missense_variant	16/44	1	NM_020964.3	P4	Q9HCE0-1

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

GnomAD3 exomes

AF:

0.000557

AC:

139

AN:

249570

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

135402

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 SAS exome

AF:

0.0000327

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

Gnomad4 AFR exome

AF:

0.0103

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00232

AC:

354

AN:

152350

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00818

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000427

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:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Vici syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2022	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 24, 2018

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2021

- -

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

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

MutationTaster

Benign

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over