rs2291627

chr15-39967647-A-Cchr15-39967647-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001013703.4(EIF2AK4):c.1321A>C(p.Ile441Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,614,002 control chromosomes in the GnomAD database, including 16,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2351 hom., cov: 31)
  • Exomes 𝑓: 0.11 (13852 hom.)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.33

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EIF2AK4
• BP4: Computational evidence support a benign effect (MetaRNN=3.8290024E-4).
• BP6: Variant 15-39967647-A-C is Benign according to our data. Variant chr15-39967647-A-C is described in ClinVar as [Benign]. Clinvar id is 381213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39967647-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.1321A>C	p.Ile441Leu	missense_variant	9/39	ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.1321A>C	p.Ile441Leu	missense_variant	9/39	2	NM_001013703.4	P1
EIF2AK4	ENST00000559624.5	c.1321A>C	p.Ile441Leu	missense_variant	9/11	1
EIF2AK4	ENST00000560855.5	c.739A>C	p.Ile247Leu	missense_variant	5/34	5

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22314 AN: 151994 Hom.: 2347 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.0980

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0892

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.150 AC: 37441 AN: 249534 Hom.: 4640 AF XY: 0.149 AC XY: 20196 AN XY: 135384

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.545

Gnomad SAS exome AF: 0.186

Gnomad FIN exome AF: 0.0968

Gnomad NFE exome AF: 0.0881

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.113 AC: 165434 AN: 1461890 Hom.: 13852 Cov.: 36 AF XY: 0.115 AC XY: 83509 AN XY: 727244

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.506

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.0881

Gnomad4 OTH exome AF: 0.144

GnomAD4 genome AF: 0.147 AC: 22341 AN: 152112 Hom.: 2351 Cov.: 31 AF XY: 0.149 AC XY: 11063 AN XY: 74374

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.533

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.0980

Gnomad4 NFE AF: 0.0893

Gnomad4 OTH AF: 0.151

Alfa AF: 0.110 Hom.: 3298

Bravo AF: 0.152

TwinsUK AF: 0.0885 AC: 328

ALSPAC AF: 0.0913 AC: 352

ESP6500AA AF: 0.191 AC: 762

ESP6500EA AF: 0.0885 AC: 739

ExAC AF: 0.149 AC: 18011

Asia WGS AF: 0.349 AC: 1210 AN: 3478

EpiCase AF: 0.0998

EpiControl AF: 0.0981

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Familial pulmonary capillary hemangiomatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.83
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D;T
MetaRNN	Benign	0.00038	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.63	N;N
MutationTaster	Benign	0.76	P;P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.010	N;N
Sift	Benign	1.0	T;T
Sift4G	Benign	0.71	T;T
Polyphen		0.0020	B;B
Vest4		0.11
MPC		0.23
ClinPred		0.0085	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.048
gMVP		0.56

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: rs2291627; hg19: chr15-40259848; COSMIC: COSV55465079;