rs144860976

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020964.3(EPG5):​c.4039A>C​(p.Asn1347His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00529 in 1,614,114 control chromosomes in the GnomAD database, including 33 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: š‘“ 0.0040 ( 1 hom., cov: 32)
Exomes š‘“: 0.0054 ( 32 hom. )

Consequence

EPG5
NM_020964.3 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 2.30
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]

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=0.0058216155).
BP6
Variant 18-45910687-T-G is Benign according to our data. Variant chr18-45910687-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225029.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr18-45910687-T-G is described in Lovd as [Likely_benign]. Variant chr18-45910687-T-G is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00397 (605/152262) while in subpopulation NFE AF= 0.00629 (428/68024). AF 95% confidence interval is 0.0058. There are 1 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 32 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPG5NM_020964.3 linkc.4039A>C p.Asn1347His missense_variant Exon 23 of 44 ENST00000282041.11 NP_066015.2 Q9HCE0-1Q9BTI0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EPG5ENST00000282041.11 linkc.4039A>C p.Asn1347His missense_variant Exon 23 of 44 1 NM_020964.3 ENSP00000282041.4 Q9HCE0-1

Frequencies

GnomAD3 genomes
AF:
0.00398
AC:
605
AN:
152144
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00190
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00207
Gnomad FIN
AF:
0.00735
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00629
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00433
AC:
1080
AN:
249410
Hom.:
7
AF XY:
0.00460
AC XY:
623
AN XY:
135340
show subpopulations
Gnomad AFR exome
AF:
0.00123
Gnomad AMR exome
AF:
0.000898
Gnomad ASJ exome
AF:
0.00328
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00265
Gnomad FIN exome
AF:
0.00756
Gnomad NFE exome
AF:
0.00639
Gnomad OTH exome
AF:
0.00496
GnomAD4 exome
AF:
0.00543
AC:
7941
AN:
1461852
Hom.:
32
Cov.:
31
AF XY:
0.00550
AC XY:
3997
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.00110
Gnomad4 ASJ exome
AF:
0.00264
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00282
Gnomad4 FIN exome
AF:
0.00668
Gnomad4 NFE exome
AF:
0.00618
Gnomad4 OTH exome
AF:
0.00493
GnomAD4 genome
AF:
0.00397
AC:
605
AN:
152262
Hom.:
1
Cov.:
32
AF XY:
0.00390
AC XY:
290
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.00120
Gnomad4 AMR
AF:
0.00190
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00207
Gnomad4 FIN
AF:
0.00735
Gnomad4 NFE
AF:
0.00629
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00576
Hom.:
25
Bravo
AF:
0.00329
TwinsUK
AF:
0.00701
AC:
26
ALSPAC
AF:
0.00649
AC:
25
ESP6500AA
AF:
0.00133
AC:
5
ESP6500EA
AF:
0.00692
AC:
57
ExAC
AF:
0.00450
AC:
544
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00583
EpiControl
AF:
0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:4
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 30, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

EPG5: BP4, BS2 -

Oct 02, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Jul 18, 2013
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

not specified Benign:1
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

EPG5-related disorder Benign:1
Jan 28, 2024
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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

Vici syndrome Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
0.094
BayesDel_addAF
Benign
-0.62
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Benign
0.013
T;T
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.075
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.65
.;T
M_CAP
Benign
0.0038
T
MetaRNN
Benign
0.0058
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.7
L;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-1.5
N;.
REVEL
Benign
0.023
Sift
Benign
0.094
T;.
Sift4G
Benign
0.32
T;.
Polyphen
0.0010
B;B
Vest4
0.18
MVP
0.17
MPC
0.32
ClinPred
0.0091
T
GERP RS
5.2
Varity_R
0.13
gMVP
0.17

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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.

Other links and lift over

dbSNP: rs144860976; hg19: chr18-43490652; COSMIC: COSV99958514; API