chr15-39939532-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_001013703.4(EIF2AK4):c.172G>C(p.Val58Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,457,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
EIF2AK4
NM_001013703.4 missense
NM_001013703.4 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 4.59
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, EIF2AK4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.17961815).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EIF2AK4 | NM_001013703.4 | c.172G>C | p.Val58Leu | missense_variant | 2/39 | ENST00000263791.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EIF2AK4 | ENST00000263791.10 | c.172G>C | p.Val58Leu | missense_variant | 2/39 | 2 | NM_001013703.4 | P1 | |
EIF2AK4 | ENST00000559624.5 | c.172G>C | p.Val58Leu | missense_variant | 2/11 | 1 | |||
EIF2AK4 | ENST00000560648.1 | c.172G>C | p.Val58Leu | missense_variant | 2/4 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248176Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134604
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457790Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725050
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ExAC
?
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1
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2024 | The c.172G>C (p.V58L) alteration is located in exon 2 (coding exon 2) of the EIF2AK4 gene. This alteration results from a G to C substitution at nucleotide position 172, causing the valine (V) at amino acid position 58 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
Sift
Benign
T;T;T
Sift4G
Benign
T;T;D
Polyphen
B;B;.
Vest4
MutPred
Gain of catalytic residue at V58 (P = 0.0981);Gain of catalytic residue at V58 (P = 0.0981);Gain of catalytic residue at V58 (P = 0.0981);
MVP
MPC
0.44
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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