rs119474039

Variant names:

• chr1-44875634-A-G
• rs119474039
• NM_020365.5:c.1037T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_020365.5(EIF2B3):​c.1037T>C​(p.Ile346Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I346M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2B3 NM_020365.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.66
• Publications: 10 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 1-44875634-A-G is Pathogenic according to our data. Variant chr1-44875634-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1037T>C	p.Ile346Thr	missense	Exon 9 of 12	NP_065098.1	Q9NR50-1
	EIF2B3	NM_001166588.3		c.1037T>C	p.Ile346Thr	missense	Exon 9 of 10	NP_001160060.1	Q9NR50-2
	EIF2B3	NM_001261418.2		c.1037T>C	p.Ile346Thr	missense	Exon 9 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.1037T>C	p.Ile346Thr	missense	Exon 9 of 12	ENSP00000353575.2	Q9NR50-1
	EIF2B3	ENST00000372183.7	TSL:1	c.1037T>C	p.Ile346Thr	missense	Exon 9 of 10	ENSP00000361257.3	Q9NR50-2
	EIF2B3	ENST00000620860.4	TSL:1	c.1037T>C	p.Ile346Thr	missense	Exon 9 of 11	ENSP00000483996.1	Q9NR50-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Leukoencephalopathy with vanishing white matter 3 (2)
1	-	-	not provided (1)
1	-	-	Vanishing white matter disease (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.68
Sift	Benign	0.075	T
Sift4G	Benign	0.081	T
Polyphen		0.13	B
Vest4		0.68
MutPred		0.85		Gain of disorder (P = 0.0249)
MVP		0.99
MPC		0.35
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.70
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs119474039; hg19: chr1-45341306;