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GeneBe

3-150564367-A-G

Variant summary

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

The NM_032025.5(EIF2A):c.461A>G(p.Glu154Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,599,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

EIF2A
NM_032025.5 missense

Scores

2
12
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.35
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]
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]

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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 UniProt
EIF2ANM_032025.5 linkuse as main transcriptc.461A>G p.Glu154Gly missense_variant 6/14 ENST00000460851.6
LOC124900547XR_007096128.1 linkuse as main transcript downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EIF2AENST00000460851.6 linkuse as main transcriptc.461A>G p.Glu154Gly missense_variant 6/141 NM_032025.5 P3Q9BY44-1

Frequencies

GnomAD3 genomes
AF:
0.0000658
AC:
10
AN:
152020
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000285
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000651
AC:
15
AN:
230272
Hom.:
0
AF XY:
0.0000721
AC XY:
9
AN XY:
124794
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000633
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000480
Gnomad NFE exome
AF:
0.000105
Gnomad OTH exome
AF:
0.000177
GnomAD4 exome
AF:
0.0000525
AC:
76
AN:
1446896
Hom.:
0
Cov.:
31
AF XY:
0.0000445
AC XY:
32
AN XY:
719104
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000474
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000567
Gnomad4 NFE exome
AF:
0.0000579
Gnomad4 OTH exome
AF:
0.0000670
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000285
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000746
AC:
9

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 submitterclinical testingAmbry GeneticsDec 28, 2022The c.461A>G (p.E154G) alteration is located in exon 6 (coding exon 6) of the EIF2A gene. This alteration results from a A to G substitution at nucleotide position 461, causing the glutamic acid (E) at amino acid position 154 to be replaced by a glycine (G). 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
Uncertain
0.40
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.13
Cadd
Pathogenic
26
Dann
Pathogenic
1.0
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Benign
0.065
D
MetaRNN
Uncertain
0.67
D;D;D;D
MetaSVM
Benign
-0.75
T
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-5.6
D;D;D;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.0030
D;D;D;D
Sift4G
Uncertain
0.022
D;D;D;D
Polyphen
0.61
.;P;.;.
Vest4
0.86
MVP
0.72
MPC
0.57
ClinPred
0.84
D
GERP RS
6.2
Varity_R
0.63
gMVP
0.64

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: rs190403466; hg19: chr3-150282154; API