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GeneBe

3-150572093-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032025.5(EIF2A):c.947C>G(p.Pro316Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

EIF2A
NM_032025.5 missense

Scores

9
4
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EIF2ANM_032025.5 linkuse as main transcriptc.947C>G p.Pro316Arg missense_variant 10/14 ENST00000460851.6
LOC124900547XR_007096128.1 linkuse as main transcriptn.241-4987G>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EIF2AENST00000460851.6 linkuse as main transcriptc.947C>G p.Pro316Arg missense_variant 10/141 NM_032025.5 P3Q9BY44-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152084
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152084
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

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 GeneticsFeb 21, 2024The c.947C>G (p.P316R) alteration is located in exon 10 (coding exon 10) of the EIF2A gene. This alteration results from a C to G substitution at nucleotide position 947, causing the proline (P) at amino acid position 316 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
0.81
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.17
Cadd
Pathogenic
28
Dann
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Benign
-0.29
T
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.7
D;D;D;D
REVEL
Uncertain
0.53
Sift
Uncertain
0.011
D;D;D;D
Sift4G
Benign
0.063
T;T;D;T
Polyphen
0.95
.;P;.;.
Vest4
0.90
MutPred
0.78
.;Gain of methylation at P316 (P = 0.0391);.;.;
MVP
0.86
MPC
0.56
ClinPred
0.99
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.43
gMVP
0.71

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: rs1724561363; hg19: chr3-150289880; API