rs113994048
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_003907.3(EIF2B5):c.318A>T(p.Leu106Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_003907.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2B5 | NM_003907.3 | c.318A>T | p.Leu106Phe | missense_variant, splice_region_variant | 2/16 | ENST00000648915.2 | |
EIF2B5 | XM_047449148.1 | c.318A>T | p.Leu106Phe | missense_variant, splice_region_variant | 2/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2B5 | ENST00000648915.2 | c.318A>T | p.Leu106Phe | missense_variant, splice_region_variant | 2/16 | NM_003907.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251402Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135862
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727230
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 28, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2023 | Reported with a second EIF2B5 variant, phase unknown, in patients with vanishing white matter disease in published literature (Leegwater et al., 2001; Turon-Vinas et al., 2014; Slynko et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29382480, 12707859, 31418856, 9710032, 18263758, 14572143, 16998732, 16807905, 20838246, 25089094, 33084218, 28252636, 35012964, 33432707, 11704758) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 106 of the EIF2B5 protein (p.Leu106Phe). This variant is present in population databases (rs113994048, gnomAD 0.03%). This missense change has been observed in individuals with leukoencephalopathy with vanishing white matter (PMID: 11704758, 25089094, 31418856). ClinVar contains an entry for this variant (Variation ID: 195203). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects EIF2B5 function (PMID: 14993275). For these reasons, this variant has been classified as Pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 13, 2017 | - - |
Vanishing white matter disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at