15-39934206-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001013703.4(EIF2AK4):c.11G>C(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000624 in 1,569,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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
• PP2: Missense variant where missense usually causes diseases, EIF2AK4
• BP4: Computational evidence support a benign effect (MetaRNN=0.13321695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.11G>C	p.Gly4Ala	missense_variant	1/39	ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.11G>C	p.Gly4Ala	missense_variant	1/39	2	NM_001013703.4	P1
EIF2AK4	ENST00000559624.5	c.11G>C	p.Gly4Ala	missense_variant	1/11	1
EIF2AK4	ENST00000560648.1	c.11G>C	p.Gly4Ala	missense_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151970 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000636 AC: 11 AN: 173088 Hom.: 0 AF XY: 0.0000731 AC XY: 7 AN XY: 95738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000194

Gnomad FIN exome AF: 0.000286

Gnomad NFE exome AF: 0.0000284

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000628 AC: 89 AN: 1417700 Hom.: 0 Cov.: 29 AF XY: 0.0000868 AC XY: 61 AN XY: 702380

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: 0.000280

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.0000385

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000428 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EIF2AK4 protein function. This variant has not been reported in the literature in individuals affected with EIF2AK4-related conditions. This variant is present in population databases (rs780175001, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4 of the EIF2AK4 protein (p.Gly4Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Benign	0.96
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.52	T;T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	0.88	N;N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.62	N;N;N
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.27	T;D;T
Polyphen		0.24	B;B;.
Vest4		0.28
MutPred		0.16		Gain of MoRF binding (P = 0.102);Gain of MoRF binding (P = 0.102);Gain of MoRF binding (P = 0.102);
MVP		0.89
MPC		0.25
ClinPred		0.056	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.47

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;