1-44881722-C-T

Position:

chr1-44881722-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The ENST00000360403.7(EIF2B3):c.674G>A(p.Arg225Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,928 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225P) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

EIF2B3
ENST00000360403.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.67

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a turn (size 3) in uniprot entity EI2BG_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000360403.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-44881722-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1285271.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 1-44881722-C-T is Pathogenic according to our data. Variant chr1-44881722-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-44881722-C-T 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.674G>A	p.Arg225Gln	missense_variant	7/12	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7 linkuse as main transcript	c.674G>A	p.Arg225Gln	missense_variant	7/12	1	NM_020365.5	ENSP00000353575	P1	Q9NR50-1
EIF2B3	ENST00000372183.7 linkuse as main transcript	c.674G>A	p.Arg225Gln	missense_variant	7/10	1		ENSP00000361257		Q9NR50-2
EIF2B3	ENST00000620860.4 linkuse as main transcript	c.674G>A	p.Arg225Gln	missense_variant	7/11	1		ENSP00000483996		Q9NR50-3
EIF2B3	ENST00000439363.5 linkuse as main transcript	c.137G>A	p.Arg46Gln	missense_variant	3/7	3		ENSP00000396985

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251422

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000665

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Nov 30, 2023	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 225 of the EIF2B3 protein (p.Arg225Gln). This variant is present in population databases (rs113994024, gnomAD 0.006%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11835386, 15776425, 19158808, 25761052). ClinVar contains an entry for this variant (Variation ID: 4437). 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. Experimental studies have shown that this missense change affects EIF2B3 function (PMID: 33517449). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

.;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.079

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.5

M;M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

.;N;N

REVEL

Pathogenic

0.76

Sift

Uncertain

0.013

.;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

1.0

D;P;D

Vest4

0.86

MutPred

0.79

Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);

MVP

0.96

MPC

0.43

ClinPred

0.80

GERP RS

5.8

Varity_R

0.48

gMVP

0.60

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