rs755139046

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020964.3(EPG5):c.2956C>G(p.Pro986Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P986L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

EPG5
NM_020964.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.37

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.065217555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3 link	c.2956C>G	p.Pro986Ala	missense_variant	Exon 16 of 44	ENST00000282041.11	NP_066015.2	Q9HCE0-1Q9BTI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11 link	c.2956C>G	p.Pro986Ala	missense_variant	Exon 16 of 44	1	NM_020964.3	ENSP00000282041.4		Q9HCE0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249560

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vici syndrome

Uncertain:1

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline with alanine at codon 986 of the EPG5 protein (p.Pro986Ala). The proline residue is weakly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs755139046, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with EPG5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.0031

T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.072

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.53

.;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N

PhyloP100

4.4

PrimateAI

Benign

0.41

PROVEAN

Benign

0.82

N;.

REVEL

Benign

0.13

Sift

Benign

0.96

T;.

Sift4G

Benign

0.44

T;.

Polyphen

0.0040

B;B

Vest4

0.28

MutPred

0.28

Loss of phosphorylation at Y982 (P = 0.1561);Loss of phosphorylation at Y982 (P = 0.1561);

MVP

0.24

MPC

0.14

ClinPred

0.24

GERP RS

5.8

Varity_R

0.078

gMVP

0.095

Mutation Taster

=96/4

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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rs755139046

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over