rs2291627

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.33

Publications

39 publications found

Variant links:

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]

EIF2AK4 Gene-Disease associations (from GenCC):

pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
pulmonary venoocclusive disease 2
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
heritable pulmonary arterial hypertension
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulmonary venoocclusive disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EIF2AK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

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 VariationId is 381213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.1321A>C	p.Ile441Leu	missense_variant	Exon 9 of 39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EIF2AK4	ENST00000263791.10 link	c.1321A>C	p.Ile441Leu	missense_variant	Exon 9 of 39	2	NM_001013703.4	ENSP00000263791.5
EIF2AK4	ENST00000559624.5 link	c.1321A>C	p.Ile441Leu	missense_variant	Exon 9 of 11	1		ENSP00000453148.1
EIF2AK4	ENST00000560855.5 link	c.736A>C	p.Ile246Leu	missense_variant	Exon 5 of 34	5		ENSP00000453575.1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22314

AN:

151994

Hom.:

2347

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.150

AC:

37441

AN:

249534

AF XY:

0.149

show subpopulations

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 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.:

AF XY:

0.115

AC XY:

83509

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.220

AC:

7370

AN:

33480

American (AMR)

AF:

0.128

AC:

5732

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

3397

AN:

26136

East Asian (EAS)

AF:

0.506

AC:

20088

AN:

39700

South Asian (SAS)

AF:

0.184

AC:

15893

AN:

86258

European-Finnish (FIN)

AF:

0.100

AC:

5353

AN:

53420

Middle Eastern (MID)

AF:

0.155

AC:

892

AN:

5768

European-Non Finnish (NFE)

AF:

0.0881

AC:

97999

AN:

1112010

Other (OTH)

AF:

0.144

AC:

8710

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

9933

19867

29800

39734

49667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4004

8008

12012

16016

20020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.147

AC:

22341

AN:

152112

Hom.:

2351

Cov.:

AF XY:

0.149

AC XY:

11063

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.212

AC:

8810

AN:

41468

American (AMR)

AF:

0.124

AC:

1890

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

444

AN:

3472

East Asian (EAS)

AF:

0.533

AC:

2750

AN:

5156

South Asian (SAS)

AF:

0.201

AC:

967

AN:

4812

European-Finnish (FIN)

AF:

0.0980

AC:

1039

AN:

10602

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0893

AC:

6070

AN:

67998

Other (OTH)

AF:

0.151

AC:

319

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

911

1823

2734

3646

4557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

250

500

750

1000

1250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.115

Hom.:

6548

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 04, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial pulmonary capillary hemangiomatosis

Benign:1

Nov 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.063

.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.00038

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.63

N;N

PhyloP100

1.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.075

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

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.048

gMVP

0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over