rs1555883384
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001958.5(EEF1A2):c.1150G>C(p.Gly384Arg) variant causes a missense change. 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
EEF1A2
NM_001958.5 missense
NM_001958.5 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 5.89
Genes affected
EEF1A2 (HGNC:3192): (eukaryotic translation elongation factor 1 alpha 2) This gene encodes an isoform of the alpha subunit of the elongation factor-1 complex, which is responsible for the enzymatic delivery of aminoacyl tRNAs to the ribosome. This isoform (alpha 2) is expressed in brain, heart and skeletal muscle, and the other isoform (alpha 1) is expressed in brain, placenta, lung, liver, kidney, and pancreas. This gene may be critical in the development of ovarian cancer. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001958.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, EEF1A2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.888
PP5
?
Variant 20-63489032-C-G is Pathogenic according to our data. Variant chr20-63489032-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 542650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EEF1A2 | NM_001958.5 | c.1150G>C | p.Gly384Arg | missense_variant | 7/8 | ENST00000217182.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EEF1A2 | ENST00000217182.6 | c.1150G>C | p.Gly384Arg | missense_variant | 7/8 | 1 | NM_001958.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 33 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2018 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with EEF1A2-related disease. However, it has been observed to be de novo in an individual with infantile-onset epilepsy and developmental delay (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 384 of the EEF1A2 protein (p.Gly384Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Epilepsy Neurogenetics Initiative, Children's Hospital of Philadelphia | Feb 13, 2020 | The EEF1A2 c.1150G>C; p.Gly384Arg variant has been identified in an individual with neonatal onset focal seizures, focal status epilepticus, infantile spasms, and tonic seizures. This individual has profound global developmental delays, hyperreflexia, cortical visual impairment, and a congenital heart defect characterized by coarctation of aorta and ventricular septal defect. The variant is de novo in this individual, is absent from population databases (ExAC, gnomAD), and is predicted to have a damaging effect on the protein by in silico models. Therefore, this variant has been classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of MoRF binding (P = 0.0279);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at