rs780889226
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_020964.3(EPG5):c.7333C>T(p.Arg2445Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000558 in 1,613,386 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
EPG5
NM_020964.3 stop_gained
NM_020964.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.25
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-45857962-G-A is Pathogenic according to our data. Variant chr18-45857962-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 570218.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.7333C>T | p.Arg2445Ter | stop_gained | 42/44 | ENST00000282041.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPG5 | ENST00000282041.11 | c.7333C>T | p.Arg2445Ter | stop_gained | 42/44 | 1 | NM_020964.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249306Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135262
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461190Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726908
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Vici syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change creates a premature translational stop signal (p.Arg2445*) 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). This variant is present in population databases (rs780889226, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Vici syndrome (PMID: 26917586). ClinVar contains an entry for this variant (Variation ID: 570218). For these reasons, this variant has been classified as Pathogenic. - |
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-strong => PVS1 downgraded in strength to Strong. - |
EPG5-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2024 | The EPG5 c.7333C>T variant is predicted to result in premature protein termination (p.Arg2445*). This variant has been reported in the apparently homozygous state in an individual with Vici syndrome (Table 1, Byrne S et al 2016. PubMed ID: 26917586). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in EPG5 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -21
Find out detailed SpliceAI scores and Pangolin per-transcript scores at