rs28937596

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_003907.3(EIF2B5):ā€‹c.1882T>Cā€‹(p.Trp628Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

9
8
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
Variant 3-184144111-T-C is Pathogenic according to our data. Variant chr3-184144111-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 5943.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EIF2B5NM_003907.3 linkuse as main transcriptc.1882T>C p.Trp628Arg missense_variant 14/16 ENST00000648915.2 NP_003898.2 Q13144
EIF2B5XM_011513265.1 linkuse as main transcriptc.1132T>C p.Trp378Arg missense_variant 10/12 XP_011511567.1
EIF2B5XM_011513266.4 linkuse as main transcriptc.1045T>C p.Trp349Arg missense_variant 9/11 XP_011511568.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EIF2B5ENST00000648915.2 linkuse as main transcriptc.1882T>C p.Trp628Arg missense_variant 14/16 NM_003907.3 ENSP00000497160.1 Q13144

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 5 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2001- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
31
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.43
T;.;T
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.84
.;T;T
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Uncertain
2.7
M;.;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.4
D;.;.
REVEL
Pathogenic
0.91
Sift
Uncertain
0.011
D;.;.
Sift4G
Pathogenic
0.0010
D;.;.
Polyphen
1.0
D;.;D
Vest4
0.93
MutPred
0.85
Gain of methylation at W628 (P = 0.0382);.;Gain of methylation at W628 (P = 0.0382);
MVP
0.88
MPC
1.3
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.84
gMVP
0.86

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: rs28937596; hg19: chr3-183861899; API