rs587777102
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001013703.4(EIF2AK4):βc.1392delβ(p.Arg465ValfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000053 ( 0 hom., cov: 32)
Exomes π: 0.000051 ( 0 hom. )
Consequence
EIF2AK4
NM_001013703.4 frameshift
NM_001013703.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.95
Genes affected
EIF2AK4 (HGNC:19687): (eukaryotic translation initiation factor 2 alpha kinase 4) This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2. [provided by RefSeq, Mar 2014]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-39967716-GT-G is Pathogenic according to our data. Variant chr15-39967716-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 97064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2AK4 | NM_001013703.4 | c.1392del | p.Arg465ValfsTer38 | frameshift_variant | 9/39 | ENST00000263791.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2AK4 | ENST00000263791.10 | c.1392del | p.Arg465ValfsTer38 | frameshift_variant | 9/39 | 2 | NM_001013703.4 | P1 | |
EIF2AK4 | ENST00000559624.5 | c.1392del | p.Arg465ValfsTer38 | frameshift_variant | 9/11 | 1 | |||
EIF2AK4 | ENST00000560855.5 | c.808del | p.Arg271ValfsTer38 | frameshift_variant | 5/34 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152172Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
8
AN:
152172
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249578Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135408
GnomAD3 exomes
AF:
AC:
4
AN:
249578
Hom.:
AF XY:
AC XY:
2
AN XY:
135408
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000506 AC: 74AN: 1461894Hom.: 0 Cov.: 35 AF XY: 0.0000413 AC XY: 30AN XY: 727248
GnomAD4 exome
AF:
AC:
74
AN:
1461894
Hom.:
Cov.:
35
AF XY:
AC XY:
30
AN XY:
727248
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74336
GnomAD4 genome
?
AF:
AC:
8
AN:
152172
Hom.:
Cov.:
32
AF XY:
AC XY:
5
AN XY:
74336
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Familial pulmonary capillary hemangiomatosis Pathogenic:3
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Sep 14, 2022 | This EIF2AK4 variant has been reported in individuals and families with pulmonary venoocclusive disease or pulmonary capillary hemangiomatosis. The variant (rs587777102) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 8/152172 total alleles; 0.00526%; no homozygotes). It has been reported in ClinVar (Variation ID 97064). This frameshift variant results in a premature stop codon in exon 9 of 39, likely leading to nonsense-mediated decay and lack of protein production. We consider c.1392delT in EIF2AK4 to be pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2024 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24292273, 27684876, 36653758, 36451176, 30285736, 24135949, 28972005, 32581362, 24784157) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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