NM_001958.5:c.364G>A

Variant names:

• chr20-63495062-C-T
• rs786205866
• NM_001958.5:c.364G>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001958.5(EEF1A2):​c.364G>A​(p.Glu122Lys) variant causes a missense 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000774988: Experimental studies have shown that this missense change affects EEF1A2 function (PMID:3066688)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: EEF1A2 NM_001958.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 7.80
• Publications: 21 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000774988: Experimental studies have shown that this missense change affects EEF1A2 function (PMID: 3066688).; SCV001746716: PS3:Supporting
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001958.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 20-63495062-C-T is Pathogenic according to our data. Variant chr20-63495062-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001958.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEF1A2	NM_001958.5	MANE Select	c.364G>A	p.Glu122Lys	missense	Exon 4 of 8	NP_001949.1	Q05639

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EEF1A2	ENST00000217182.6	TSL:1 MANE Select	c.364G>A	p.Glu122Lys	missense	Exon 4 of 8	ENSP00000217182.3	Q05639
	EEF1A2	ENST00000298049.13	TSL:1	c.364G>A	p.Glu122Lys	missense	Exon 4 of 9	ENSP00000298049.9	A0A2U3TZH3
	EEF1A2	ENST00000706949.1		c.364G>A	p.Glu122Lys	missense	Exon 4 of 9	ENSP00000516669.1	A0A9L9PYI8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.000286 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Developmental and epileptic encephalopathy, 33 (5)
5	-	-	not provided (5)
3	-	-	Intellectual disability, autosomal dominant 38 (3)
1	-	-	EEF1A2-related developmental and degenerative epileptic-dyskinetic encephalopathy (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.86		Gain of methylation at E122 (P = 0.0026)
MVP		0.67
MPC		3.1
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		1.0
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786205866; hg19: chr20-62126415;