chr1-44850965-G-A

Variant names:

• chr1-44850965-G-A
• NM_020365.5:c.1345C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020365.5(EIF2B3):​c.1345C>T​(p.Leu449Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B3 NM_020365.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

Genes affected

EIF2B3 (HGNC:3259): (eukaryotic translation initiation factor 2B subunit gamma) The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

EIF2B3 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19704974).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020365.5. 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
	EIF2B3	NM_020365.5	MANE Select	c.1345C>T	p.Leu449Phe	missense	Exon 12 of 12	NP_065098.1	Q9NR50-1
	EIF2B3	NM_001261418.2		c.*35C>T		3_prime_UTR	Exon 11 of 11	NP_001248347.1	Q9NR50-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.1345C>T	p.Leu449Phe	missense	Exon 12 of 12	ENSP00000353575.2	Q9NR50-1
	EIF2B3	ENST00000620860.4	TSL:1	c.*35C>T		3_prime_UTR	Exon 11 of 11	ENSP00000483996.1	Q9NR50-3
	EIF2B3	ENST00000852384.1		c.1408C>T	p.Leu470Phe	missense	Exon 13 of 13	ENSP00000522443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.00098
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.034	D
Sift4G	Benign	0.19	T
Polyphen		0.0030	B
Vest4		0.28
MutPred		0.33		Gain of catalytic residue at L449 (P = 0.0581)
MVP		0.98
MPC		0.28
ClinPred		0.93	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.72
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

hg19: chr1-45316637;