NM_001414.4:c.547G>T

Variant names:

• chr12-123626429-C-A
• rs863225048
• NM_001414.4:c.547G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001414.4(EIF2B1):​c.547G>T​(p.Val183Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V183V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF2B1 NM_001414.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.00
• Publications: 9 publications found

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]

EIF2B1 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 12-123626429-C-A is Pathogenic according to our data. Variant chr12-123626429-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217277.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	NM_001414.4	MANE Select	c.547G>T	p.Val183Phe	missense	Exon 6 of 9	NP_001405.1	Q14232-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	ENST00000424014.7	TSL:1 MANE Select	c.547G>T	p.Val183Phe	missense	Exon 6 of 9	ENSP00000416250.2	Q14232-1
	EIF2B1	ENST00000929734.1		c.547G>T	p.Val183Phe	missense	Exon 6 of 10	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.547G>T	p.Val183Phe	missense	Exon 6 of 10	ENSP00000527269.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.72		Gain of catalytic residue at V183 (P = 0)
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.89
Mutation Taster		=13/87	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs863225048; hg19: chr12-124110976;