rs113994048

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The ENST00000432569.2(EIF2B5):c.318A>T(p.Leu106Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,074 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

EIF2B5
ENST00000432569.2 missense

Scores

Splicing: ADA: 0.09947

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -0.00400

Publications

9 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

PP5

Variant 3-184136734-A-T is Pathogenic according to our data. Variant chr3-184136734-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 195203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B5	NM_003907.3 link	c.318A>T	p.Leu106Phe	missense_variant, splice_region_variant	Exon 2 of 16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_047449148.1 link	c.318A>T	p.Leu106Phe	missense_variant, splice_region_variant	Exon 2 of 11		XP_047305104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 link	c.318A>T	p.Leu106Phe	missense_variant, splice_region_variant	Exon 2 of 16		NM_003907.3	ENSP00000497160.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251402

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111996

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 106 of the EIF2B5 protein (p.Leu106Phe). This variant is present in population databases (rs113994048, gnomAD 0.03%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 25089094, 31418856). ClinVar contains an entry for this variant (Variation ID: 195203). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects EIF2B5 function (PMID: 14993275). For these reasons, this variant has been classified as Pathogenic. -

Apr 28, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported with a second EIF2B5 variant, phase unknown, in patients with vanishing white matter disease in published literature (Leegwater et al., 2001; Turon-Vinas et al., 2014; Slynko et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29382480, 12707859, 31418856, 9710032, 18263758, 14572143, 16998732, 16807905, 20838246, 25089094, 33084218, 28252636, 35012964, 33432707, 11704758) -

Inborn genetic diseases

Pathogenic:1

Oct 13, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EIF2B5-related disorder

Pathogenic:1

Aug 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The EIF2B5 c.318A>T variant is predicted to result in the amino acid substitution p.Leu106Phe. This variant has been reported in homozygous and compound heterozygous states individuals with features consistent with leukoencephalopathy with vanishing white matter (Supplementary Table 2, Cohen et al. 2019. PubMed ID: 31418856; Esmer et al. 2017. PubMed ID: 29382480; Supplementary Table 1, Salinas et al. 2020. PubMed ID: 33084218; eTable 2, Schlüter et al. 2022. PubMed ID: 35012964; Supplementary Table 1, phasing unknown in Baldridge et al. 2017. PubMed ID: 28252636; phasing unknown in Leegwater et al. 2001. PubMed ID: 11704758). This variant is reported in 0.032% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Leukoencephalopathy with vanishing white matter 5

Pathogenic:1

Dec 29, 2023

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leukoencephalopathy with vanishing white matter 1

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.318A>T (p.Leu106Phe) in the EIF2B5 gene has been reported previously in heterozygous and homozygous states in multiple individuals affected with Vanishing white matter leukoencephalopathy. Experimental studies have shown that this missense change affects the EIF2B5 function (Turón-Viñas et al., 2014; Richardson et al., 2004). However there is no recent literature supporting experimental evidence. This variant is reported with the allele frequency (0.004%) in the gnomAD. It is submitted to ClinVar with varying interpretations as Pathogenic/ Likely Pathogenic. The amino acid Leucine at position 106 is changed to a Phenylalanine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. -

Vanishing white matter disease

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.77

.;T;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

2.0

M;.;.;M

PhyloP100

-0.0040

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.3

N;D;.;.

REVEL

Pathogenic

0.73

Sift

Benign

0.10

T;D;.;.

Sift4G

Uncertain

0.015

D;D;.;.

Polyphen

0.97

D;.;.;D

Vest4

0.79

MutPred

0.83

Gain of ubiquitination at K103 (P = 0.0719);Gain of ubiquitination at K103 (P = 0.0719);Gain of ubiquitination at K103 (P = 0.0719);Gain of ubiquitination at K103 (P = 0.0719);

MVP

0.98

MPC

0.42

ClinPred

0.66

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.70

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.099

dbscSNV1_RF

Benign

0.33

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over