rs113994074

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_003907.3(EIF2B5):​c.1157G>C​(p.Gly386Ala) variant causes a missense, splice region 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. 2/2 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G386V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

EIF2B5
NM_003907.3 missense, splice_region

Scores

11
6
2
Splicing: ADA: 0.9999
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.86
Variant links:
Genes affected
EIF2B5 (HGNC:3261): (eukaryotic translation initiation factor 2B subunit epsilon) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Nov 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-184141925-G-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EIF2B5NM_003907.3 linkuse as main transcriptc.1157G>C p.Gly386Ala missense_variant, splice_region_variant 8/16 ENST00000648915.2 NP_003898.2 Q13144
EIF2B5XM_047449148.1 linkuse as main transcriptc.1157G>C p.Gly386Ala missense_variant, splice_region_variant 8/11 XP_047305104.1
EIF2B5XM_011513265.1 linkuse as main transcriptc.407G>C p.Gly136Ala missense_variant, splice_region_variant 4/12 XP_011511567.1
EIF2B5XM_011513266.4 linkuse as main transcriptc.320G>C p.Gly107Ala missense_variant, splice_region_variant 3/11 XP_011511568.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EIF2B5ENST00000648915.2 linkuse as main transcriptc.1157G>C p.Gly386Ala missense_variant, splice_region_variant 8/16 NM_003907.3 ENSP00000497160.1 Q13144

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;.;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
.;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;.;M
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.5
D;.;.
REVEL
Pathogenic
0.93
Sift
Uncertain
0.015
D;.;.
Sift4G
Pathogenic
0.0
D;.;.
Polyphen
1.0
D;.;D
Vest4
0.92
MutPred
0.88
Loss of loop (P = 0.0986);.;Loss of loop (P = 0.0986);
MVP
0.90
MPC
0.95
ClinPred
0.99
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
SpliceAI score (max)
0.69
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.69
Position offset: 0

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: rs113994074; hg19: chr3-183859713; API