20-63493155-C-T

Variant names:

• chr20-63493155-C-T
• rs786205865
• NM_001958.5:c.754G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PM5 PP5_Very_Strong

The NM_001958.5(EEF1A2):​c.754G>A​(p.Asp252Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D252H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EEF1A2 NM_001958.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.76
• Publications: 14 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-63493155-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192251.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 20-63493155-C-T is Pathogenic according to our data. Variant chr20-63493155-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2631662.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
EEF1A2	NM_001958.5	c.754G>A	p.Asp252Asn	missense_variant	Exon 5 of 8	ENST00000217182.6	NP_001949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EEF1A2	ENST00000217182.6	c.754G>A	p.Asp252Asn	missense_variant	Exon 5 of 8	1	NM_001958.5	ENSP00000217182.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Feb 12, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

EEF1A2-related disorder Pathogenic:1

Sep 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EEF1A2 c.754G>A variant is predicted to result in the amino acid substitution p.Asp252Asn. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different substitution of the same amino acid (p.Asp252His) was reported to have occurred de novo in an individual with intellectual disability, motor delay, absent speech, autistic features, seizures, progressive microcephaly, brain malformation, and facial dysmorphology (Nakajima et al. 2015. PubMed ID: 24697219). The p.Asp252His substitution was also reported as a de novo variant in a study of individuals with severe developmental disorders (Individual DDD4K.00592 in Supplementary Table 1, McRae et al. 2017. PubMed ID: 28135719). Taken together, the c.754G>A (p.Asp252Asn) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.080	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.27
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.010	B
Vest4		0.82
MutPred		0.54		Loss of phosphorylation at Y254 (P = 0.0733);
MVP		0.65
MPC		1.6
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.79
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs786205865; hg19: chr20-62124508;