NM_001013703.4:c.1321A>G

Variant names:

• chr15-39967647-A-G
• rs2291627
• NM_001013703.4:c.1321A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 16/22 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
• Publications: 39 publications found

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 Gene-Disease associations (from GenCC):

• pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary venoocclusive disease 2

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary venoocclusive disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17953938).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013703.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	NM_001013703.4	MANE Select	c.1321A>G	p.Ile441Val	missense	Exon 9 of 39	NP_001013725.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.1321A>G	p.Ile441Val	missense	Exon 9 of 39	ENSP00000263791.5
	EIF2AK4	ENST00000559624.5	TSL:1	c.1321A>G	p.Ile441Val	missense	Exon 9 of 11	ENSP00000453148.1
	EIF2AK4	ENST00000560855.5	TSL:5	c.736A>G	p.Ile246Val	missense	Exon 5 of 34	ENSP00000453575.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 6548

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.13	N
PhyloP100		1.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.094
Sift	Benign	0.50	T
Sift4G	Benign	0.30	T
Polyphen		0.0070	B
Vest4		0.17
MutPred		0.58		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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs2291627; hg19: chr15-40259848;