rs113994049

Variant names:

• chr3-184137637-G-A
• rs113994049
• NM_003907.3:c.338G>A
• EIF2B5 p.Arg113His

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPM5PP5_Strong

The NM_003907.3(EIF2B5):c.338G>A (p.Arg113His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000512 (AC=826) in the gnomAD database across 1,614,142 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000641. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000916013: Functional studies conducted in patient cells demonstrated that this variant impacts protein function (PMID:15060152" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R113C: Pathogenic/Likely_pathogenic (ClinVar VariationId 692118, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R113= (synonymous): Likely_benign (ClinVar VariationId 1122006, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27
• Conservation: PhyloP100: 3.40
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women's Health
• leukoencephalopathy with vanishing white matter 5

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Natera, ClinGen
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EIF2B5-DT (HGNC:55202): (EIF2B5 divergent transcript)

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 11 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000916013: Functional studies conducted in patient cells demonstrated that this variant impacts protein function (PMID: 15060152; 22737209; 22952606).; SCV002061282: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 26112719) - PS3_supporting."; SCV003800952: "At least one publication reports experimental evidence evaluating an impact on protein function reporting decreased tolerance to Endoplasmic Reticulum Stress (ERS) although the magnitude of the reported findings differed significantly from truncated or deletion mutants in EIF2B5 (Chen_2015)."; SCV000322123: Published functional studies demonstrate a damaging effect with reduction of activity compared to wild-type (Li et al., 2004); SCV000957238: Experimental studies have shown that this missense change affects EIF2B5 function (PMID: 26112719).; SCV004013557: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID:15060152, 26112719; SCV004861560: Functional studies show that this alteration leads to reduced GEF activity (Liu, 2011; Li, 2004; Chen, 2015).; SCV005357161: An in vitro functional study revealed that homozygous c.338G>A (p.Arg113His) alleles have around 49 -75% of GEF elf2B activity (Fogli A. et al. 2004. PubMed ID: 15054402).
• PM2: Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000641 — borderline rare for AR gene (threshold 0.001) — PM2 supporting.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R113C: Pathogenic/Likely_pathogenic (ClinVar VariationId 692118, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R113= (synonymous): Likely_benign (ClinVar VariationId 1122006, 1 star)
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (27/27 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003907.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	NM_003907.3	MANE Select	c.338G>A	p.Arg113His	missense	Exon 3 of 16	NP_003898.2	Q13144

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B5	ENST00000648915.2	MANE Select	c.338G>A	p.Arg113His	missense	Exon 3 of 16	ENSP00000497160.1	Q13144
	EIF2B5	ENST00000481054.5	TSL:1	n.339G>A		non_coding_transcript_exon	Exon 3 of 15
	EIF2B5	ENST00000647909.1		c.338G>A	p.Arg113His	missense	Exon 3 of 16	ENSP00000498164.1	A0A3B3IUB1

Frequencies

GnomAD3 genomes AF: 0.000275 AC: 41 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000916

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0000610

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: 0.000519

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000214 AC: 54 AN: 251478 AF XY: 0.000244

Gnomad AFR exome AF: 0.0000610

Gnomad AMR exome AF: 0.0000916

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000412

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000534 AC: 785 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.000534 AC XY: 389 AN XY: 727244

African (AFR) AF: 0.000153 AC: 5 AN: 33480

American (AMR) AF: 0.000183 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000305 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000687 AC: 756 AN: 1111998

Other (OTH) AF: 0.000229 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000275 AC: 41 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000168 AC XY: 12 AN XY: 74456

African (AFR) AF: 0.0000916 AC: 4 AN: 41546

American (AMR) AF: 0.0000610 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000519 AC: 35 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000397 Hom.: 0

Bravo AF: 0.000259

Asia WGS AF: 0.000290 AC: 1 AN: 3478

EpiCase AF: 0.000488

EpiControl AF: 0.000351

Local populations

ABraOM SABE-WGS-1171 AF: 0.00214 AC: 5 AN: 2342 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Vanishing white matter disease (8)
7	-	-	Leukoencephalopathy with vanishing white matter 5 (7)
7	-	-	not provided (7)
2	-	-	See cases (2)
1	-	-	EIF2B5-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Leukoencephalopathy with vanishing white matter 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.090	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.53
Sift	Benign	0.17	T
Sift4G	Benign	0.11	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.48
Mutation Taster		=13/87	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113994049;

hg19: chr3-183855425;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar