3-184141925-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_003907.3(EIF2B5):c.1157G>T(p.Gly386Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EIF2B5 NM_003907.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.86

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_003907.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-184141925-G-T is Pathogenic according to our data. Variant chr3-184141925-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 5944.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184141925-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B5	NM_003907.3	c.1157G>T	p.Gly386Val	missense_variant, splice_region_variant	8/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.1157G>T	p.Gly386Val	missense_variant, splice_region_variant	8/11
EIF2B5	XM_011513265.1	c.407G>T	p.Gly136Val	missense_variant, splice_region_variant	4/12
EIF2B5	XM_011513266.4	c.320G>T	p.Gly107Val	missense_variant, splice_region_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.1157G>T	p.Gly386Val	missense_variant, splice_region_variant	8/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727220

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-8.3	D;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.93		Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.76		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113994074; hg19: chr3-183859713;