rs113994043

Positions:

chr3-184135551-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.18

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5951.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B5	NM_003907.3 linkuse as main transcript	c.166T>G	p.Phe56Val	missense_variant	1/16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_047449148.1 linkuse as main transcript	c.166T>G	p.Phe56Val	missense_variant	1/11		XP_047305104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2 linkuse as main transcript	c.166T>G	p.Phe56Val	missense_variant	1/16		NM_003907.3	ENSP00000497160	P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000479

AC:

AN:

208642

Hom.:

AF XY:

0.00

AC XY:

AN XY:

113324

show subpopulations

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:

AN:

1438664

Hom.:

Cov.:

AF XY:

0.00000841

AC XY:

AN XY:

713780

show subpopulations

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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Labcorp Genetics (formerly Invitae), Labcorp

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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 19, 2024

Variant summary: EIF2B5 c.166T>G (p.Phe56Val) results in a non-conservative amino acid change located in the translation initiation factor eIF-2B subunit epsilon, N-terminal domain (IPR035543) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-06 in 208642 control chromosomes (gnomAD). c.166T>G has been reported in the literature in two siblings affected with severe, infantile-onset central hypomyelination syndrome or vanishing white matter disease (Fogli_2004, Passemard_2007). These data indicate that the variant may be associated with disease. In vitro and in vivo functional assays shows reduced activity for the variant. The following publications have been ascertained in the context of this evaluation (PMID: 23335982, 15054402, 17646634, 21560189). ClinVar contains an entry for this variant (Variation ID: 5951). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

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

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.;.;M

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.72

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over