3-184140499-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_003907.3(EIF2B5):c.925G>C(p.Val309Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,614,012 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 (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 3.61

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 10 ACMG points.

PM1

In a helix (size 11) in uniprot entity EI2BE_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003907.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 3-184140499-G-C is Pathogenic according to our data. Variant chr3-184140499-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5947.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B5	NM_003907.3 link	c.925G>C	p.Val309Leu	missense_variant	Exon 7 of 16	ENST00000648915.2	NP_003898.2	Q13144
EIF2B5	XM_047449148.1 link	c.925G>C	p.Val309Leu	missense_variant	Exon 7 of 11		XP_047305104.1
EIF2B5	XM_011513265.1 link	c.175G>C	p.Val59Leu	missense_variant	Exon 3 of 12		XP_011511567.1
EIF2B5	XM_011513266.4 link	c.88G>C	p.Val30Leu	missense_variant	Exon 2 of 11		XP_011511568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 link	c.925G>C	p.Val309Leu	missense_variant	Exon 7 of 16		NM_003907.3	ENSP00000497160.1		Q13144

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000119

AC:

AN:

251458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

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 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:

0.00000274

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vanishing white matter disease

Pathogenic:1Other:1

Aug 30, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EIF2B5 c.925G>C (p.Val309Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251458 control chromosomes. c.925G>C has been reported in the literature in individuals affected with Leukoencephalopathy With Vanishing White Matter (example: Huyghe_2012,Fogli_2002). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22737209, 12499492). ClinVar contains an entry for this variant (Variation ID: 5947). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Variant associated w/severe disease -

Leukoencephalopathy with vanishing white matter 5

Pathogenic:1

Dec 24, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;T

Eigen

Benign

-0.098

Eigen_PC

Benign

0.0076

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.3

M;.;M

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0090

D;.;.

Sift4G

Uncertain

0.021

D;.;.

Polyphen

0.079

B;.;B

Vest4

0.80

MutPred

0.94

Loss of MoRF binding (P = 0.143);.;Loss of MoRF binding (P = 0.143);

MVP

0.98

MPC

0.31

ClinPred

0.81

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.79

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