rs907041830

chr3-184140584-A-Gchr3-184140584-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_003907.3(EIF2B5):c.1010A>G(p.His337Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.89

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a strand (size 2) in uniprot entity EI2BE_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003907.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184140584-A-G is Pathogenic according to our data. Variant chr3-184140584-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 590971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B5	NM_003907.3	c.1010A>G	p.His337Arg	missense_variant	7/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.1010A>G	p.His337Arg	missense_variant	7/11
EIF2B5	XM_011513265.1	c.260A>G	p.His87Arg	missense_variant	3/12
EIF2B5	XM_011513266.4	c.173A>G	p.His58Arg	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.1010A>G	p.His337Arg	missense_variant	7/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Consultorio y Laboratorio de Neurogenética, Hospital JM Ramos Mejia

Oct 29, 2018

The variant identified not been previously reported in public databases. This variant was identified in a patient diagnosed with Vanishing white matter leukodystrophy, a disease characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. We consider that these variants in compound heterozygosis are probably pathogenic because they are in a critical region and coding for the EIF2B5 gene; The gene has previously been associated with this disease as reported in the OMIM database and PubMed (Sharma et al., 2015; Woody et al., 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.35	T;.;.
Sift4G	Benign	0.30	T;.;.
Polyphen		0.94	P;.;P
Vest4		0.82
MutPred		0.33		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);
MVP		0.78
MPC		0.40
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.77
gMVP		0.76

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

Other links and lift over

dbSNP: rs907041830; hg19: chr3-183858372;