rs119474039
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
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
ENST00000360403.7 missense
Scores
7
5
7
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N
REVEL
Pathogenic
Sift
Benign
.;T;T
Sift4G
Benign
T;T;T
Polyphen
0.13, 0.62
.;B;P
Vest4
MutPred
Gain of disorder (P = 0.0249);Gain of disorder (P = 0.0249);Gain of disorder (P = 0.0249);
MVP
MPC
0.35
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at