rs113994048

Positions:

chr3-184136734-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_003907.3(EIF2B5):c.318A>T(p.Leu106Phe) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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
NM_003907.3 missense, splice_region

Scores

Splicing: ADA: 0.09947

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: -0.00400

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 195203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184136734-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B5	NM_003907.3 linkuse as main transcript	c.318A>T	p.Leu106Phe	missense_variant, splice_region_variant	2/16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_047449148.1 linkuse as main transcript	c.318A>T	p.Leu106Phe	missense_variant, splice_region_variant	2/11		XP_047305104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 linkuse as main transcript	c.318A>T	p.Leu106Phe	missense_variant, splice_region_variant	2/16		NM_003907.3	ENSP00000497160	P2

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

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251402

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135862

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2023	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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2017

- -

EIF2B5-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

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 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

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

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

MutationTaster

Benign

1.0

A;A;A

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over