rs141988913
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_020365.5(EIF2B3):c.272G>A(p.Arg91His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,906 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R91C) has been classified as Uncertain significance.
Frequency
Consequence
NM_020365.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2B3 | NM_020365.5 | c.272G>A | p.Arg91His | missense_variant | 3/12 | ENST00000360403.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2B3 | ENST00000360403.7 | c.272G>A | p.Arg91His | missense_variant | 3/12 | 1 | NM_020365.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251392Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135876
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461794Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727196
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74296
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2018 | The R91H variant in the EIF2B3 gene has been reported previously in an individual with vanishing white matter disease who was heterozygous for the R91H variant and another disease-causing variant (Robinson et al., 2014). The R91H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R91H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R91H as a likely pathogenic variant. - |
Vanishing white matter disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at