15-39967647-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001013703.4(EIF2AK4):c.1321A>G(p.Ile441Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I441L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33

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]

ACMG classification

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=0.17953938).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.1321A>G	p.Ile441Val	missense_variant	9/39	ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.1321A>G	p.Ile441Val	missense_variant	9/39	2	NM_001013703.4	P1
EIF2AK4	ENST00000559624.5	c.1321A>G	p.Ile441Val	missense_variant	9/11	1
EIF2AK4	ENST00000560855.5	c.739A>G	p.Ile247Val	missense_variant	5/34	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	18
Dann	Benign	0.56
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.13	N;N
MutationTaster	Benign	0.88	P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.15	N;N
Sift	Benign	0.50	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0070	B;B
Vest4		0.17
MutPred		0.58		Gain of ubiquitination at K440 (P = 0.0849);Gain of ubiquitination at K440 (P = 0.0849);
MVP		0.79
MPC		0.20
ClinPred		0.11	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.022
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2291627; hg19: chr15-40259848;