20-63488355-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001958.5(EEF1A2):c.1335C>A(p.Ser445Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000152 in 1,318,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S445S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

EEF1A2
NM_001958.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.0140

Publications

2 publications found

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]

EEF1A2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 33
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EEF1A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08783531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EEF1A2	NM_001958.5 link	c.1335C>A	p.Ser445Arg	missense_variant	Exon 8 of 8	ENST00000217182.6	NP_001949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EEF1A2	ENST00000217182.6 link	c.1335C>A	p.Ser445Arg	missense_variant	Exon 8 of 8	1	NM_001958.5	ENSP00000217182.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000152

AC:

AN:

1318816

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

650486

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26568

American (AMR)

AF:

0.00

AC:

AN:

26288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23050

East Asian (EAS)

AF:

0.00

AC:

AN:

27876

South Asian (SAS)

AF:

0.00

AC:

AN:

72578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5134

European-Non Finnish (NFE)

AF:

0.00000192

AC:

AN:

1043210

Other (OTH)

AF:

0.00

AC:

AN:

54040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 33

Uncertain:1

Jun 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EEF1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 864342). This variant has not been reported in the literature in individuals affected with EEF1A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 445 of the EEF1A2 protein (p.Ser445Arg). -

Inborn genetic diseases

Uncertain:1

Jun 22, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S445R variant (also known as c.1335C>A), located in coding exon 7 of the EEF1A2 gene, results from a C to A substitution at nucleotide position 1335. The serine at codon 445 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

May 23, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

PhyloP100

0.014

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.49

REVEL

Benign

0.012

Sift

Benign

0.19

Sift4G

Benign

0.16

Polyphen

0.19

Vest4

0.14

MutPred

0.22

Loss of glycosylation at S445 (P = 0.03);

MVP

0.35

MPC

1.8

ClinPred

0.22

GERP RS

0.68

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.44

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over