rs587777208

Positions:

• chr15-40008067-C-G
• chr15-40008067-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001013703.4(EIF2AK4):​c.3448C>G​(p.Arg1150Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71

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]

EIF2AK4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EIF2AK4. . Gene score misZ 2.6675 (greater than the threshold 3.09). Trascript score misZ 3.5194 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary venoocclusive disease 2, pulmonary venoocclusive disease, heritable pulmonary arterial hypertension, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.3448C>G	p.Arg1150Gly	missense_variant	25/39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.3448C>G	p.Arg1150Gly	missense_variant	25/39	2	NM_001013703.4	ENSP00000263791.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000306 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.51		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.84
MPC		0.43
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.73

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: rs587777208; hg19: chr15-40300268;