rs113994043

chr3-184135551-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_003907.3(EIF2B5):c.166T>G(p.Phe56Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000626 in 1,438,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F56C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.18

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-184135552-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 5952.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-184135551-T-G is Pathogenic according to our data. Variant chr3-184135551-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5951.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.166T>G	p.Phe56Val	missense_variant	1/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.166T>G	p.Phe56Val	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.166T>G	p.Phe56Val	missense_variant	1/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000479 AC: 1 AN: 208642 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 113324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000626 AC: 9 AN: 1438664 Hom.: 0 Cov.: 30 AF XY: 0.00000841 AC XY: 6 AN XY: 713780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000817

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 24, 2007

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 16, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EIF2B5 protein function. This variant has been observed in individual(s) with EIF2B5-related conditions (PMID: 15136673). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5951). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with valine at codon 56 of the EIF2B5 protein (p.Phe56Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;T;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;.;.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.3	D;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.012	D;D;.;.
Polyphen		1.0	D;.;.;D
Vest4		0.93
MutPred		0.96		Gain of ubiquitination at K61 (P = 0.1025);Gain of ubiquitination at K61 (P = 0.1025);Gain of ubiquitination at K61 (P = 0.1025);Gain of ubiquitination at K61 (P = 0.1025);
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs113994043; hg19: chr3-183853339;