chr15-39934236-A-C

Position:

• chr15-39934236-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001013703.4(EIF2AK4):​c.41A>C​(p.Glu14Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19

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 2 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=0.33886093).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.41A>C	p.Glu14Ala	missense_variant	1/39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.41A>C	p.Glu14Ala	missense_variant	1/39	2	NM_001013703.4	ENSP00000263791	P1
EIF2AK4	ENST00000559624.5	c.41A>C	p.Glu14Ala	missense_variant	1/11	1		ENSP00000453148
EIF2AK4	ENST00000560648.1	c.41A>C	p.Glu14Ala	missense_variant	1/4	3		ENSP00000453968

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.41A>C (p.E14A) alteration is located in exon 1 (coding exon 1) of the EIF2AK4 gene. This alteration results from a A to C substitution at nucleotide position 41, causing the glutamic acid (E) at amino acid position 14 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	.;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.67	T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.86	L;L;.
MutationTaster	Benign	0.70	D;D;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.49	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.22	B;B;.
Vest4		0.51
MutPred		0.14		Gain of MoRF binding (P = 0.0623);Gain of MoRF binding (P = 0.0623);Gain of MoRF binding (P = 0.0623);
MVP		0.82
MPC		0.25
ClinPred		0.89	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-40226437;