rs113994064

Positions:

chr3-184140518-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_003907.3(EIF2B5):c.944G>A(p.Arg315His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R315C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.09

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a turn (size 5) in uniprot entity EI2BE_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_003907.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-184140517-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 598970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 3-184140518-G-A is Pathogenic according to our data. Variant chr3-184140518-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184140518-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
EIF2B5	NM_003907.3 linkuse as main transcript	c.944G>A	p.Arg315His	missense_variant	7/16	ENST00000648915.2
EIF2B5	XM_047449148.1 linkuse as main transcript	c.944G>A	p.Arg315His	missense_variant	7/11
EIF2B5	XM_011513265.1 linkuse as main transcript	c.194G>A	p.Arg65His	missense_variant	3/12
EIF2B5	XM_011513266.4 linkuse as main transcript	c.107G>A	p.Arg36His	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2 linkuse as main transcript	c.944G>A	p.Arg315His	missense_variant	7/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251418

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727246

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2022	Functional studies in lymphocytes from a patient who had the R315H variant as well as another EIF2B5 variant suggest reduction of guanine exchange activity compared to wild-type; however, additional studies are needed to validate the functional effect of this variant on its own (Horzinski et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21307862, 17646634, 26162493, 20016818, 15136673, 11704758, 33084218, 34745209, 20958979) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 315 of the EIF2B5 protein (p.Arg315His). This variant is present in population databases (rs113994064, gnomAD 0.007%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 17646634; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5950). 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 not expected to disrupt EIF2B5 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg315 amino acid residue in EIF2B5. Other variant(s) that disrupt this residue have been observed in individuals with EIF2B5-related conditions (PMID: 11704758, 15136673, 21307862), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Vanishing white matter disease

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 11, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Leukoencephalopathy with vanishing white matter 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 24, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

T;.;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.2

L;.;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.66

PROVEAN

Benign

1.4

N;.;.

REVEL

Uncertain

0.60

Sift

Benign

0.37

T;.;.

Sift4G

Benign

0.31

T;.;.

Polyphen

0.071

B;.;B

Vest4

0.90

MVP

0.99

MPC

0.35

ClinPred

0.31

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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