chr3-184143455-A-T

Position:

• chr3-184143455-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003907.3(EIF2B5):​c.1759A>T​(p.Ile587Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I587V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

EIF2B5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B5	NM_003907.3	c.1759A>T	p.Ile587Leu	missense_variant	13/16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_011513265.1	c.1009A>T	p.Ile337Leu	missense_variant	9/12		XP_011511567.1
EIF2B5	XM_011513266.4	c.922A>T	p.Ile308Leu	missense_variant	8/11		XP_011511568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2	c.1759A>T	p.Ile587Leu	missense_variant	13/16		NM_003907.3	ENSP00000497160.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	5.3e-7	P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.64	N;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.21	T;.;.
Sift4G	Benign	0.16	T;.;.
Polyphen		0.20	B;.;B
Vest4		0.46
MutPred		0.36		Loss of ubiquitination at K582 (P = 0.0613);.;Loss of ubiquitination at K582 (P = 0.0613);
MVP		0.71
MPC		0.36
ClinPred		0.77	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;