rs119474039

Positions:

• chr1-44875634-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000360403.7(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 Pathogenic (no stars). 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 ENST00000360403.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.66

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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]. Clinvar id is 4440.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-44875634-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.1037T>C	p.Ile346Thr	missense_variant	9/12	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.1037T>C	p.Ile346Thr	missense_variant	9/12	1	NM_020365.5	ENSP00000353575	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Leukoencephalopathy with vanishing white matter 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2009

- -

Vanishing white matter disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

Chinese founder variant -

Computational scores

Source: dbNSFP v4.3

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;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.1	M;M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	.;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.075	.;T;T
Sift4G	Benign	0.081	T;T;T
Polyphen		0.13, 0.62	.;B;P
Vest4		0.68
MutPred		0.85		Gain of disorder (P = 0.0249);Gain of disorder (P = 0.0249);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

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs119474039; hg19: chr1-45341306;