3-184143455-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003907.3(EIF2B5):c.1759A>G(p.Ile587Val) variant causes a missense change. The variant allele was found at a frequency of 0.338 in 1,613,776 control chromosomes in the GnomAD database, including 94,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.33 ( 8620 hom., cov: 32)

Exomes 𝑓: 0.34 ( 86164 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.21

Publications

54 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011105835).

BP6

Variant 3-184143455-A-G is Benign according to our data. Variant chr3-184143455-A-G is described in ClinVar as Benign. ClinVar VariationId is 94381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B5	NM_003907.3 link	c.1759A>G	p.Ile587Val	missense_variant	Exon 13 of 16	ENST00000648915.2	NP_003898.2	Q13144
EIF2B5	XM_011513265.1 link	c.1009A>G	p.Ile337Val	missense_variant	Exon 9 of 12		XP_011511567.1
EIF2B5	XM_011513266.4 link	c.922A>G	p.Ile308Val	missense_variant	Exon 8 of 11		XP_011511568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 link	c.1759A>G	p.Ile587Val	missense_variant	Exon 13 of 16		NM_003907.3	ENSP00000497160.1		Q13144

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50514

AN:

151894

Hom.:

8602

Cov.:

show subpopulations

Gnomad AFR

AF:

0.317

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.345

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.538

Gnomad SAS

AF:

0.415

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.324

Gnomad OTH

AF:

0.319

GnomAD2 exomes

AF:

0.351

AC:

88308

AN:

251430

AF XY:

0.351

show subpopulations

Gnomad AFR exome

AF:

0.321

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.275

Gnomad EAS exome

AF:

0.523

Gnomad FIN exome

AF:

0.310

Gnomad NFE exome

AF:

0.320

Gnomad OTH exome

AF:

0.330

GnomAD4 exome

AF:

0.339

AC:

495690

AN:

1461764

Hom.:

86164

Cov.:

AF XY:

0.340

AC XY:

247577

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.315

AC:

10529

AN:

33478

American (AMR)

AF:

0.380

AC:

16975

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

7090

AN:

26134

East Asian (EAS)

AF:

0.543

AC:

21573

AN:

39696

South Asian (SAS)

AF:

0.401

AC:

34608

AN:

86256

European-Finnish (FIN)

AF:

0.306

AC:

16364

AN:

53402

Middle Eastern (MID)

AF:

0.262

AC:

1512

AN:

5768

European-Non Finnish (NFE)

AF:

0.330

AC:

366843

AN:

1111912

Other (OTH)

AF:

0.334

AC:

20196

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

20425

40850

61276

81701

102126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12140

24280

36420

48560

60700

<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:

0.333

AC:

50559

AN:

152012

Hom.:

8620

Cov.:

AF XY:

0.337

AC XY:

25037

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.317

AC:

13151

AN:

41484

American (AMR)

AF:

0.346

AC:

5272

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.276

AC:

959

AN:

3470

East Asian (EAS)

AF:

0.539

AC:

2778

AN:

5158

South Asian (SAS)

AF:

0.414

AC:

1994

AN:

4812

European-Finnish (FIN)

AF:

0.309

AC:

3258

AN:

10554

Middle Eastern (MID)

AF:

0.308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.324

AC:

22051

AN:

67976

Other (OTH)

AF:

0.325

AC:

685

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1733

3466

5199

6932

8665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.329

Hom.:

38054

Bravo

AF:

0.333

TwinsUK

AF:

0.333

AC:

1233

ALSPAC

AF:

0.329

AC:

1268

ESP6500AA

AF:

0.327

AC:

1441

ESP6500EA

AF:

0.329

AC:

2827

ExAC

AF:

0.350

AC:

42462

Asia WGS

AF:

0.474

AC:

1647

AN:

3478

EpiCase

AF:

0.323

EpiControl

AF:

0.319

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 17, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 06, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Vanishing white matter disease

Benign:3

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.068

T;.;T

Eigen

Benign

-0.022

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

.;T;T

MetaRNN

Benign

0.0011

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.73

N;.;N

PhyloP100

5.2

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.19

N;.;.

REVEL

Uncertain

0.42

Sift

Benign

0.27

T;.;.

Sift4G

Benign

0.60

T;.;.

Polyphen

0.26

B;.;B

Vest4

0.057

MPC

0.24

ClinPred

0.019

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.38

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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