rs113994043

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_003907.3(EIF2B5):c.166T>G(p.Phe56Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000626 in 1,438,664 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F56C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.18

Publications

5 publications found

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]

EIF2B5 links:

EIF2B5-DT (HGNC:55202): (EIF2B5 divergent transcript)

EIF2B5-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-184135552-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 5952.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 3-184135551-T-G is Pathogenic according to our data. Variant chr3-184135551-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5951.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B5	NM_003907.3 link	c.166T>G	p.Phe56Val	missense_variant	Exon 1 of 16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_047449148.1 link	c.166T>G	p.Phe56Val	missense_variant	Exon 1 of 11		XP_047305104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 link	c.166T>G	p.Phe56Val	missense_variant	Exon 1 of 16		NM_003907.3	ENSP00000497160.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000479

AC:

AN:

208642

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000626

AC:

AN:

1438664

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

713780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32724

American (AMR)

AF:

0.00

AC:

AN:

42092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

38114

South Asian (SAS)

AF:

0.00

AC:

AN:

82850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4780

European-Non Finnish (NFE)

AF:

0.00000817

AC:

AN:

1101942

Other (OTH)

AF:

0.00

AC:

AN:

59346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000655

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 5

Pathogenic:2

Jun 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 24, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

May 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces phenylalanine with valine at codon 56 of the EIF2B5 protein (p.Phe56Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with EIF2B5-related conditions (PMID: 15136673). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5951). 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 expected to disrupt EIF2B5 protein function. -

not specified

Uncertain:1

Jun 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EIF2B5 c.166T>G (p.Phe56Val) results in a non-conservative amino acid change located in the translation initiation factor eIF-2B subunit epsilon, N-terminal domain (IPR035543) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4.8e-06 in 208642 control chromosomes. c.166T>G has been observed in two siblings affected with severe, infantile-onset central hypomyelination syndrome or vanishing white matter disease (Fogli_2004, Passemard_2007). These data indicate that the variant may be associated with disease. In vitro and in vivo functional assays shows reduced activity (50-90% of wild type) for the variant (Liu_2011). The following publications have been ascertained in the context of this evaluation (PMID: 23335982, 15054402, 17646634, 21560189). ClinVar contains an entry for this variant (Variation ID: 5951). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;T;.;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.;M

PhyloP100

7.2

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.3

D;D;.;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Uncertain

0.012

D;D;.;.

Polyphen

1.0

D;.;.;D

Vest4

0.93

MutPred

0.96

Gain of ubiquitination at K61 (P = 0.1025);Gain of ubiquitination at K61 (P = 0.1025);Gain of ubiquitination at K61 (P = 0.1025);Gain of ubiquitination at K61 (P = 0.1025);

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

4.9

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.97

gMVP

0.95

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over