rs843358

chr3-184143455-A-Gchr3-184143455-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8620 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86164 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.21

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 94381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184143455-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
EIF2B5	NM_003907.3	c.1759A>G	p.Ile587Val	missense_variant	13/16	ENST00000648915.2
EIF2B5	XM_011513265.1	c.1009A>G	p.Ile337Val	missense_variant	9/12
EIF2B5	XM_011513266.4	c.922A>G	p.Ile308Val	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.1759A>G	p.Ile587Val	missense_variant	13/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50514 AN: 151894 Hom.: 8602 Cov.: 32

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

GnomAD3 exomes AF: 0.351 AC: 88308 AN: 251430 Hom.: 16116 AF XY: 0.351 AC XY: 47763 AN XY: 135888

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 SAS exome AF: 0.402

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.: 51 AF XY: 0.340 AC XY: 247577 AN XY: 727184

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.380

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.543

Gnomad4 SAS exome AF: 0.401

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.330

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.333 AC: 50559 AN: 152012 Hom.: 8620 Cov.: 32 AF XY: 0.337 AC XY: 25037 AN XY: 74318

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.539

Gnomad4 SAS AF: 0.414

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.324

Gnomad4 OTH AF: 0.325

Alfa AF: 0.329 Hom.: 20790

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Vanishing white matter disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.068	T;.;T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0011	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.73	N;.;N
MutationTaster	Benign	0.0000013	P;P
PrimateAI	Uncertain	0.57	T
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	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs843358; hg19: chr3-183861243; COSMIC: COSV56604028; COSMIC: COSV56604028;