rs886039346

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong

The NM_001958.5(EEF1A2):​c.1267C>T​(p.Arg423Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

EEF1A2
NM_001958.5 missense, splice_region

Scores

7
6
6

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 5.27
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the EEF1A2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 34 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 4.8166 (above the threshold of 3.09). Trascript score misZ: 6.0564 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, undetermined early-onset epileptic encephalopathy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 33.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.751
PP5
Variant 20-63488423-G-A is Pathogenic according to our data. Variant chr20-63488423-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EEF1A2NM_001958.5 linkc.1267C>T p.Arg423Cys missense_variant, splice_region_variant Exon 8 of 8 ENST00000217182.6 NP_001949.1 Q05639

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EEF1A2ENST00000217182.6 linkc.1267C>T p.Arg423Cys missense_variant, splice_region_variant Exon 8 of 8 1 NM_001958.5 ENSP00000217182.3 Q05639

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1299564
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
639820
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Dec 31, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (impaired protein synthesis) (Carvill et al., 2020); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26633542, 30377530, 12869201, 27441201, 30109124, 32196822, 28911200, 30370994, 32062104, 31477274) -

Jan 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 33 Pathogenic:1Other:1
Sep 07, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 265111). This missense change has been observed in individual(s) with clinical features of EEF1A2-related conditions (PMID: 27441201, 28911200, 30109124). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 423 of the EEF1A2 protein (p.Arg423Cys). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -

-
GenomeConnect - Invitae Patient Insights Network
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 10-23-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Inborn genetic diseases Pathogenic:1
Sep 21, 2017
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.87
D
Eigen
Benign
-0.037
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.87
D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.75
D
MetaSVM
Benign
-0.42
T
MutationAssessor
Pathogenic
3.4
M
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-4.5
D
REVEL
Uncertain
0.32
Sift
Benign
0.043
D
Sift4G
Benign
0.062
T
Polyphen
0.054
B
Vest4
0.53
MutPred
0.77
Loss of MoRF binding (P = 0.0014);
MVP
0.78
MPC
2.3
ClinPred
0.93
D
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.43
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs886039346; hg19: chr20-62119776; API