3-184140122-G-C

Position:

• chr3-184140122-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_003907.3(EIF2B5):​c.808G>C​(p.Asp270His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2B5 NM_003907.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.59

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 9) in uniprot entity EI2BE_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_003907.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184140122-G-C is Pathogenic according to our data. Variant chr3-184140122-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40178.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-184140122-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B5	NM_003907.3	c.808G>C	p.Asp270His	missense_variant	6/16	ENST00000648915.2
EIF2B5	XM_047449148.1	c.808G>C	p.Asp270His	missense_variant	6/11
EIF2B5	XM_011513265.1	c.58G>C	p.Asp20His	missense_variant	2/12
EIF2B5	XM_011513266.4	c.-94G>C		5_prime_UTR_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B5	ENST00000648915.2	c.808G>C	p.Asp270His	missense_variant	6/16		NM_003907.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Aug 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.0	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.15	T;.;.
Sift4G	Benign	0.19	T;.;.
Polyphen		0.33	B;.;B
Vest4		0.86
MutPred		0.51		Gain of glycosylation at T268 (P = 0.0181);.;Gain of glycosylation at T268 (P = 0.0181);
MVP		0.96
MPC		0.41
ClinPred		0.58	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.42
gMVP		0.65

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: rs397514646; hg19: chr3-183857910;