NM_003907.3:c.166T>G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_003907.3(EIF2B5):āc.166T>Gā(p.Phe56Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000626 in 1,438,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_003907.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000479 AC: 1AN: 208642Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 113324
GnomAD4 exome AF: 0.00000626 AC: 9AN: 1438664Hom.: 0 Cov.: 30 AF XY: 0.00000841 AC XY: 6AN XY: 713780
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Leukoencephalopathy with vanishing white matter 5 Pathogenic:2
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not provided Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces phenylalanine with valine at codon 56 of the EIF2B5 protein (p.Phe56Val). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with EIF2B5-related conditions (PMID: 15136673). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EIF2B5 protein function. -
not specified Uncertain:1
Variant summary: EIF2B5 c.166T>G (p.Phe56Val) results in a non-conservative amino acid change located in the translation initiation factor eIF-2B subunit epsilon, N-terminal domain (IPR035543) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-06 in 208642 control chromosomes (gnomAD). c.166T>G has been reported in the literature in two siblings affected with severe, infantile-onset central hypomyelination syndrome or vanishing white matter disease (Fogli_2004, Passemard_2007). These data indicate that the variant may be associated with disease. In vitro and in vivo functional assays shows reduced activity for the variant. The following publications have been ascertained in the context of this evaluation (PMID: 23335982, 15054402, 17646634, 21560189). ClinVar contains an entry for this variant (Variation ID: 5951). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at