rs2307105

Positions:

• chr15-39973598-A-C
• chr15-39973598-A-G
• chr15-39973598-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001013703.4(EIF2AK4):​c.1667A>C​(p.Glu556Ala) 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. 16/21 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. E556G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53

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 Likely_benign. Variant got -1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06759575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.1667A>C	p.Glu556Ala	missense_variant	11/39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.1667A>C	p.Glu556Ala	missense_variant	11/39	2	NM_001013703.4	ENSP00000263791	P1
EIF2AK4	ENST00000559624.5	c.1667A>C	p.Glu556Ala	missense_variant	11/11	1		ENSP00000453148
EIF2AK4	ENST00000560855.5	c.1085A>C	p.Glu362Ala	missense_variant	7/34	5		ENSP00000453575

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457726 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 725064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.048	.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.18	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.55	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.076
Sift	Benign	0.66	T;T
Sift4G	Benign	0.85	T;T
Polyphen		0.0	B;B
Vest4		0.030
MutPred		0.26		Loss of disorder (P = 0.0764);Loss of disorder (P = 0.0764);
MVP		0.77
MPC		1.1
ClinPred		0.33	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2307105; hg19: chr15-40265799;