rs843358

Variant names:

• chr3-184143455-A-G
• rs843358
• NM_003907.3:c.1759A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-184143455-A-G
• chr3-184143455-A-C
• chr3-184143455-A-T

Variant summary

Our verdict is Benign. The variant received -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 (★★). 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.21
• Publications: 54 publications found

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-DT (HGNC:55202): (EIF2B5 divergent transcript)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003907.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	NM_003907.3	MANE Select	c.1759A>G	p.Ile587Val	missense	Exon 13 of 16	NP_003898.2	Q13144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	ENST00000648915.2	MANE Select	c.1759A>G	p.Ile587Val	missense	Exon 13 of 16	ENSP00000497160.1	Q13144
	EIF2B5	ENST00000481054.5	TSL:1	n.2152A>G		non_coding_transcript_exon	Exon 13 of 15
	EIF2B5	ENST00000647909.1		c.1783A>G	p.Ile595Val	missense	Exon 13 of 16	ENSP00000498164.1	A0A3B3IUB1

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

GnomAD2 exomes AF: 0.351 AC: 88308 AN: 251430 AF XY: 0.351

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

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

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

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: 90 AN: 292

European-Non Finnish (NFE) AF: 0.324 AC: 22051 AN: 67976

Other (OTH) AF: 0.325 AC: 685 AN: 2106

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	3	Vanishing white matter disease (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.022
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.73	N
PhyloP100		5.2
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
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
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

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