rs863225052

Positions:

• chr12-123622674-A-C
• chr12-123622674-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001414.4(EIF2B1):​c.715T>G​(p.Phe239Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 32)
• Consequence: EIF2B1 NM_001414.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.30

Genes affected

EIF2B1 (HGNC:3257): (eukaryotic translation initiation factor 2B subunit alpha) 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, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-123622674-A-C is Pathogenic according to our data. Variant chr12-123622674-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 217282.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B1	NM_001414.4	c.715T>G	p.Phe239Val	missense_variant	8/9	ENST00000424014.7	NP_001405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B1	ENST00000424014.7	c.715T>G	p.Phe239Val	missense_variant	8/9	1	NM_001414.4	ENSP00000416250.2
EIF2B1	ENST00000539951.5	c.600T>G	p.Ser200Ser	synonymous_variant	6/7	5		ENSP00000438060.1
EIF2B1	ENST00000534960	c.*122T>G		3_prime_UTR_variant	6/6	5		ENSP00000443172.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vanishing white matter disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.90	P
Vest4		0.55
MutPred		0.50		Gain of catalytic residue at F235 (P = 0.0191);
MVP		0.99
MPC		0.98
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.94
gMVP		0.95

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

Other links and lift over

dbSNP: rs863225052; hg19: chr12-124107221;