rs113994022

Positions:

chr1-44978349-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_020365.5(EIF2B3):c.260C>T(p.Ala87Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,916 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

EIF2B3
NM_020365.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 9.21

Variant links:

Genes affected

EIF2B3 (HGNC:3259): (eukaryotic translation initiation factor 2B subunit gamma) The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

EIF2B3 links:

EIF2B3 (HGNC:):

EIF2B3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 1-44978349-G-A is Pathogenic according to our data. Variant chr1-44978349-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44978349-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B3	NM_020365.5 linkuse as main transcript	c.260C>T	p.Ala87Val	missense_variant	3/12	ENST00000360403.7	NP_065098.1	Q9NR50-1Q9HA31

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7 linkuse as main transcript	c.260C>T	p.Ala87Val	missense_variant	3/12	1	NM_020365.5	ENSP00000353575.2		Q9NR50-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251402

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000163

AC:

239

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000201

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000112

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000186

Hom.:

Bravo

AF:

0.0000945

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27864579, 31418856, 11835386, 25079571, 22312164, 23115207, 16998732, 14572143, 26162493, 31589614, 33084218, 27535533, 35783294) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the EIF2B3 protein (p.Ala87Val). This variant is present in population databases (rs113994022, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of leukoencephalopathy with vanishing white matter (PMID: 11835386, 22312164, 25079571, 31418856). ClinVar contains an entry for this variant (Variation ID: 4439). 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 EIF2B3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EIF2B3 function (PMID: 33517449). For these reasons, this variant has been classified as Pathogenic. -

Vanishing white matter disease

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 22, 2023	Variant summary: EIF2B3 c.260C>T (p.Ala87Val) results in a non-conservative amino acid change located in the Nucleotidyl transferase domain (IPR005835) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 251402 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in EIF2B3 causing Leukoencephalopathy With Vanishing White Matter (8.8e-05 vs 0.00032), allowing no conclusion about variant significance. c.260C>T has been reported in the literature in multiple individuals affected with Leukoencephalopathy With Vanishing White Matter and related clinical features (Example: Robinson_2014, van der Knapp_2002, Cohen_2020, LaPiana_2012 etc.) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=1), Likely Pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	French-Canadian (non-Cree) founder variant -

EIF2B3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The EIF2B3 c.260C>T variant is predicted to result in the amino acid substitution p.Ala87Val. This variant was reported in homozygous and compound heterozygous state in multiple individuals with leukoencephalopathy with vanishing white matter (van der Knaap et al. 2002. PubMed ID: 11835386; La Piana et al. 2012. PubMed ID: 22312164; Ghezzi et al. 2012. PubMed ID: 23115207; Robinson et al. 2014. PubMed ID: 25079571; Cohen et al. 2019. PubMed ID: 31418856; Capalbo et al. 2019. PubMed ID: 31589614 Table S1; Salinas et al. 2020. PubMed ID: 33084218 Table S1). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Leukoencephalopathy with vanishing white matter 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

.;D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.7

M;M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.1

.;D;D

REVEL

Pathogenic

0.87

Sift

Benign

0.073

.;T;D

Sift4G

Benign

0.063

T;T;T

Polyphen

0.98

D;D;D

Vest4

0.97

MVP

0.97

MPC

0.79

ClinPred

0.82

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.77

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.

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