rs28939717

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_003907.3(EIF2B5):โ€‹c.271A>Gโ€‹(p.Thr91Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (โ˜…โ˜…).

Frequency

Genomes: ๐‘“ 0.000039 ( 0 hom., cov: 33)
Exomes ๐‘“: 0.000053 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

7
6
6

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.32
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 Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-184136687-A-G is Pathogenic according to our data. Variant chr3-184136687-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EIF2B5NM_003907.3 linkc.271A>G p.Thr91Ala missense_variant 2/16 ENST00000648915.2 NP_003898.2 Q13144
EIF2B5XM_047449148.1 linkc.271A>G p.Thr91Ala missense_variant 2/11 XP_047305104.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EIF2B5ENST00000648915.2 linkc.271A>G p.Thr91Ala missense_variant 2/16 NM_003907.3 ENSP00000497160.1 Q13144

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152212
Hom.:
0
Cov.:
33
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251470
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000791
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.0000536
AC XY:
39
AN XY:
727240
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:
0.0000692
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74486
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000114
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Vanishing white matter disease Pathogenic:5Other:1
not provided, no classification providedliterature onlyGeneReviews-Dutch founder variant, associated w/relatively mild disease -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 03, 2019The p.Thr91Ala variant in EIF2B5 has been reported in the homozygous or compound heterozygous state in at least 15 individuals with leukoencephalopathy with vanishing white matter and segregated with disease in 3 affected individuals from 3 families (Leegwater 2001, Li 2004, Kantor 2005, Horzinski 2010, van der Lei 2010, Liu 2011). It has also been reported by other clinical laboratories in ClinVar (Variation ID # 5942) and has been identified in 0.008% (10/129180) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Li 2004, Dietrich 2005, Horzinski 2010, Liu 2011). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive leukoencephalopathy with vanishing white matter. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Moderate, PS3_Supporting. -
Likely pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityMar 24, 2017- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The EIF2B5 c.271A>G (p.Thr91Ala) missense variant has been well-described in the literature as a pathogenic variant for childhood ataxia with central nervous system hypomyelination and vanishing white matter, which is also known as leukoencephalopathy with vanishing white matter (VWM). Leegwater et al. (2001) studied 41 individuals with VWM from 35 families, and found the p.Thr91Ala variant in a homozygous state in seven individuals (including two sibling pairs), and in a compound heterozygous state in four individuals. The p.Thr91Ala variant was found as part of a shared ancestral haplotype. Van der Lei et al. (2010) compared the phenotypes 184 individuals with VWM and a few select genotypes, including eight individuals homozygous for the p.Thr91Ala variant, and seven individuals compound heterozygous for the p.Thr91Ala variant and a missense variant. The authors suggest that the variable VWM phenotype is determined by the combination of both variants, although the p.Thr91Ala variant is generally associated with an intermediate/moderate phenotype. Functional studies demonstrated that the p.Thr91Ala variant protein has a reduced ability to form eIF2B holocomplexes and that holocomplexes containing the p.Thr91Ala variant had reduced, but not absent, enzymatic activity (Li et al. 2004; Liu et al. 2011). The p.Thr91Ala variant was absent from at least 210 control chromosomes and is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Thr91Ala variant is classified as pathogenic for childhood ataxia with central nervous system hypomyelination and vanishing white matter. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsSep 03, 2021- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Jul 05, 2020- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 02, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 91 of the EIF2B5 protein (p.Thr91Ala). This variant is present in population databases (rs28939717, gnomAD 0.009%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 15136673, 20975056, 21560189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5942). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EIF2B5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EIF2B5 function (PMID: 15060152). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 04, 2024Published functional studies indicate that T91A is associated with a decrease in guanine nucleotide-exchange factor activity (PMID: 21560189); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 11704758, 21560189) -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TรผbingenJun 17, 2021- -
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
0.66
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;T;.;T
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
.;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.63
D;D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Benign
0.95
L;.;.;L
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.2
N;N;.;.
REVEL
Pathogenic
0.83
Sift
Benign
0.25
T;T;.;.
Sift4G
Benign
0.18
T;D;.;.
Polyphen
1.0
D;.;.;D
Vest4
0.77
MVP
0.95
MPC
0.32
ClinPred
0.25
T
GERP RS
5.7
Varity_R
0.50
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs28939717; hg19: chr3-183854475; API