rs587776941

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1PM2PP3PP5_Moderate

The NM_020964.3(EPG5):​c.2575G>T​(p.Glu859*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000030 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

EPG5
NM_020964.3 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.32
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 Pathogenic. Variant got 13 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;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 18-45925881-C-A is Pathogenic according to our data. Variant chr18-45925881-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 39983.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPG5NM_020964.3 linkc.2575G>T p.Glu859* stop_gained Exon 14 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.2575G>T p.Glu859* stop_gained Exon 14 of 44 1 NM_020964.3 ENSP00000282041.4 Q9HCE0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000297
AC:
4
AN:
1347148
Hom.:
0
Cov.:
29
AF XY:
0.00000300
AC XY:
2
AN XY:
666040
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000154
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000189
Gnomad4 OTH exome
AF:
0.0000181
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Vici syndrome Pathogenic:2
Jan 01, 2013
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 17, 2019
SIB Swiss Institute of Bioinformatics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

This variant is interpreted as a 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 => Predicted nullvariant in a gene where LOF is a known mechanism of disease. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:23222957). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
47
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.42
GERP RS
5.5

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.60
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.60
Position offset: -43

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: rs587776941; hg19: chr18-43505847; COSMIC: COSV56346108; API