rs587777106
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_001013703.4(EIF2AK4):c.1754G>A(p.Arg585Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,042 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 Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
EIF2AK4
NM_001013703.4 missense
NM_001013703.4 missense
Scores
11
5
1
Clinical Significance
Conservation
PhyloP100: 9.69
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, EIF2AK4
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.86
PP5
?
Variant 15-39973685-G-A is Pathogenic according to our data. Variant chr15-39973685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 97068.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2AK4 | NM_001013703.4 | c.1754G>A | p.Arg585Gln | missense_variant | 11/39 | ENST00000263791.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2AK4 | ENST00000263791.10 | c.1754G>A | p.Arg585Gln | missense_variant | 11/39 | 2 | NM_001013703.4 | P1 | |
EIF2AK4 | ENST00000559624.5 | c.1754G>A | p.Arg585Gln | missense_variant | 11/11 | 1 | |||
EIF2AK4 | ENST00000560855.5 | c.1172G>A | p.Arg391Gln | missense_variant | 7/34 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249558Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135396
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727226
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Familial pulmonary capillary hemangiomatosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of phosphorylation at S584 (P = 0.1076);Loss of phosphorylation at S584 (P = 0.1076);
MVP
MPC
2.3
ClinPred
D
GERP RS
Varity_R
gMVP
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