Variant 3-150563596-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032025.5(EIF2A):c.374A>G(p.Gln125Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000942 in 1,379,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

EIF2A
NM_032025.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41

Variant links:

Genes affected

EIF2A (HGNC:3254): (eukaryotic translation initiation factor 2A) This gene encodes a eukaryotic translation initiation factor that catalyzes the formation of puromycin-sensitive 80 S preinitiation complexes and the poly(U)-directed synthesis of polyphenylalanine at low concentrations of Mg2+. This gene should not be confused with eIF2-alpha (EIF2S1, Gene ID: 1965), the alpha subunit of the eIF2 translation initiation complex. Although both of these proteins function in binding initiator tRNA to the 40 S ribosomal subunit, the encoded protein does so in a codon-dependent manner, whereas eIF2 complex requires GTP. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

EIF2A links:

SERP1 (HGNC:10759): (stress associated endoplasmic reticulum protein 1) Predicted to be involved in endoplasmic reticulum unfolded protein response and protein glycosylation. Predicted to act upstream of or within several processes, including multicellular organism aging; positive regulation of organ growth; and positive regulation of peptide hormone secretion. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

SERP1 links:

EIF2A (HGNC:):

EIF2A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2A	NM_032025.5 linkuse as main transcript	c.374A>G	p.Gln125Arg	missense_variant	5/14	ENST00000460851.6	NP_114414.2	Q9BY44-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2A	ENST00000460851.6 linkuse as main transcript	c.374A>G	p.Gln125Arg	missense_variant	5/14	1	NM_032025.5	ENSP00000417229.1		Q9BY44-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

136814

Hom.:

AF XY:

0.0000139

AC XY:

AN XY:

72072

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000544

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000114

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000942

AC:

AN:

1379944

Hom.:

Cov.:

AF XY:

0.0000103

AC XY:

AN XY:

679960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000662

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000135

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.000140

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.374A>G (p.Q125R) alteration is located in exon 5 (coding exon 5) of the EIF2A gene. This alteration results from a A to G substitution at nucleotide position 374, causing the glutamine (Q) at amino acid position 125 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;T;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.65

D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.1

.;M;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Uncertain

0.39

Sift

Benign

0.038

D;D;T;D

Sift4G

Benign

0.16

T;T;D;T

Polyphen

1.0

.;D;.;.

Vest4

0.69

MutPred

0.56

.;Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);.;

MVP

0.80

MPC

0.53

ClinPred

0.81

GERP RS

5.7

Varity_R

0.50

gMVP

0.77

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over