15-39934206-G-T

Variant names:

• chr15-39934206-G-T
• rs780175001
• NM_001013703.4:c.11G>T

Variant summary

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

The NM_001013703.4(EIF2AK4):​c.11G>T​(p.Gly4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3809781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.11G>T	p.Gly4Val	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.11G>T	p.Gly4Val	missense_variant	Exon 1 of 39	2	NM_001013703.4	ENSP00000263791.5
EIF2AK4	ENST00000559624.5	c.11G>T	p.Gly4Val	missense_variant	Exon 1 of 11	1		ENSP00000453148.1
EIF2AK4	ENST00000560648.1	c.11G>T	p.Gly4Val	missense_variant	Exon 1 of 4	3		ENSP00000453968.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417700 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 702380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000256

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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	.;T;T
Eigen	Benign	0.019
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.85	P;P;.
Vest4		0.36
MutPred		0.26		Gain of MoRF binding (P = 0.07);Gain of MoRF binding (P = 0.07);Gain of MoRF binding (P = 0.07);
MVP		0.91
MPC		0.29
ClinPred		0.71	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.27
gMVP		0.50

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: rs780175001; hg19: chr15-40226407;