rs886040857
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001415.4(EIF2S3):c.1394_1397del(p.Ile465SerfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
EIF2S3
NM_001415.4 frameshift
NM_001415.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.34
Genes affected
EIF2S3 (HGNC:3267): (eukaryotic translation initiation factor 2 subunit gamma) The protein encoded by this gene is the largest subunit of a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40 S ribosomal subunit. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0197 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-24076756-ACAAT-A is Pathogenic according to our data. Variant chrX-24076756-ACAAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-24076756-ACAAT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2S3 | NM_001415.4 | c.1394_1397del | p.Ile465SerfsTer4 | frameshift_variant | 12/12 | ENST00000253039.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2S3 | ENST00000253039.9 | c.1394_1397del | p.Ile465SerfsTer4 | frameshift_variant | 12/12 | 1 | NM_001415.4 | P1 | |
EIF2S3 | ENST00000457332.1 | n.151-584_151-581del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2016 | The c.1394_1397delTCAA variant in the EIF2S3 gene has been reported previously in a family segregating a form of syndromic X-linked intellectual disability characterized by neonatal hypoglycemia, severe microcephaly, developmental delay, micropenis, epileptic seizures and early death (Moortgat et al., 2016). In this family, the c.1394_1397delTCAA variant was present in three obligate carrier female relatives and absent in three healthy male relatives, however, no affected male relatives were available for testing (Moorgat et al., 2016). The c.1394_1397delTCAA variant causes a frameshift starting with codon Isoleucine 465, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Ile465SerfsX4. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1394_1397delTCAA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.1394_1397delTCAA variant as a likely pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 20, 2016 | - - |
MEHMO syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Experimental Endocrinology, Slovak Academy of Sciences | Oct 07, 2016 | found in 3 independent MEHMO patients, not found in ExAC, functional study confirms effect on eIF2 function - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 18, 2018 | - - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at