rs1064794256

Variant names:

• chr3-184144175-T-C
• rs1064794256
• NM_003907.3:c.1946T>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_003907.3(EIF2B5):​c.1946T>C​(p.Ile649Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,884 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.28

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 3-184144175-T-C is Pathogenic according to our data. Variant chr3-184144175-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B5	NM_003907.3	c.1946T>C	p.Ile649Thr	missense_variant	Exon 14 of 16	ENST00000648915.2	NP_003898.2
EIF2B5	XM_011513265.1	c.1196T>C	p.Ile399Thr	missense_variant	Exon 10 of 12		XP_011511567.1
EIF2B5	XM_011513266.4	c.1109T>C	p.Ile370Thr	missense_variant	Exon 9 of 11		XP_011511568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B5	ENST00000648915.2	c.1946T>C	p.Ile649Thr	missense_variant	Exon 14 of 16		NM_003907.3	ENSP00000497160.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727246

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: 0.0000144

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vanishing white matter disease Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leukoencephalopathy with vanishing white matter 5 Pathogenic:1

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jun 20, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with EIF2B5-related leukoencephalopathy, however no evidence was provided to evaluate pathogenicity (Pronk et al., 2006; van der Lei et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect as this variant leads to a significant decrease in protein function as compared to wild-type protein (Liu et al., 2011; De Almeida et al., 2013); This variant is associated with the following publications: (PMID: 23335982, 16632312, 22430157, 16807905, 21560189) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.5	M;.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D;.;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0090	D;.;.
Sift4G	Benign	0.20	T;.;.
Polyphen		0.96	D;.;D
Vest4		0.91
MutPred		0.84		Loss of stability (P = 0.0283);.;Loss of stability (P = 0.0283);
MVP		0.90
MPC		0.94
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.51

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: rs1064794256; hg19: chr3-183861963;