rs374991853

Variant names:

• chr15-39934270-C-A
• rs374991853
• NM_001013703.4:c.75C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-39934270-C-A
• chr15-39934270-C-G
• chr15-39934270-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013703.4(EIF2AK4):​c.75C>A​(p.His25Gln) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.541

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25098437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.75C>A	p.His25Gln	missense_variant	Exon 1 of 39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.75C>A	p.His25Gln	missense_variant	Exon 1 of 39	2	NM_001013703.4	ENSP00000263791.5
EIF2AK4	ENST00000559624.5	c.75C>A	p.His25Gln	missense_variant	Exon 1 of 11	1		ENSP00000453148.1
EIF2AK4	ENST00000560648.1	c.75C>A	p.His25Gln	missense_variant	Exon 1 of 4	3		ENSP00000453968.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.042	.;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.29	N;N;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D;D;T
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.011	B;P;.
Vest4		0.33
MutPred		0.36		Loss of catalytic residue at L27 (P = 0.1566);Loss of catalytic residue at L27 (P = 0.1566);Loss of catalytic residue at L27 (P = 0.1566);
MVP		0.66
MPC		0.37
ClinPred		0.89	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.33

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: rs374991853; hg19: chr15-40226471;