rs863225064
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_020964.3(EPG5):c.7447C>T(p.Arg2483Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000105 in 1,612,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
EPG5
NM_020964.3 stop_gained
NM_020964.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 6.88
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0379 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 18-45855683-G-A is Pathogenic according to our data. Variant chr18-45855683-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPG5 | NM_020964.3 | c.7447C>T | p.Arg2483Ter | stop_gained | 43/44 | ENST00000282041.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPG5 | ENST00000282041.11 | c.7447C>T | p.Arg2483Ter | stop_gained | 43/44 | 1 | NM_020964.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152108Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249184Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135192
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460166Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9AN XY: 726530
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Vici syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 16, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Jan 17, 2019 | This variant is interpreted as a Likely pathogenic for Vici syndrome, autosomal recessive The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Moderate => PVS1 downgraded in strength to Moderate. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:26917586). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 217320). This premature translational stop signal has been observed in individual(s) with Vici syndrome (PMID: 32558422). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2483*) in the EPG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EPG5 are known to be pathogenic (PMID: 23222957, 23674064). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A
Vest4
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at