15-39973598-A-G

Variant names:

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.1667A>G(p.Glu556Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.936 in 1,609,762 control chromosomes in the GnomAD database, including 709,825 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 0.91 ( 63882 hom., cov: 31)

Exomes 𝑓: 0.94 ( 645943 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.53

Publications

36 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=6.1075446E-7).

BP6

Variant 15-39973598-A-G is Benign according to our data. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in CliVar as Benign. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.1667A>G	p.Glu556Gly	missense_variant	Exon 11 of 39	ENST00000263791.10	NP_001013725.2	Q9P2K8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF2AK4	ENST00000263791.10 link	c.1667A>G	p.Glu556Gly	missense_variant	Exon 11 of 39	2	NM_001013703.4	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000559624.5 link	c.1667A>G	p.Glu556Gly	missense_variant	Exon 11 of 11	1		ENSP00000453148.1	Q9P2K8-3
EIF2AK4	ENST00000560855.5 link	c.1082A>G	p.Glu361Gly	missense_variant	Exon 7 of 34	5		ENSP00000453575.1	H0YME5

Frequencies

GnomAD3 genomes

AF:

0.913

AC:

138918

AN:

152114

Hom.:

63848

Cov.:

show subpopulations

Gnomad AFR

AF:

0.900

Gnomad AMI

AF:

0.904

Gnomad AMR

AF:

0.779

Gnomad ASJ

AF:

0.979

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.869

Gnomad FIN

AF:

0.895

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.963

Gnomad OTH

AF:

0.927

GnomAD2 exomes

AF:

0.880

AC:

216504

AN:

245890

AF XY:

0.891

show subpopulations

Gnomad AFR exome

AF:

0.899

Gnomad AMR exome

AF:

0.636

Gnomad ASJ exome

AF:

0.973

Gnomad EAS exome

AF:

0.785

Gnomad FIN exome

AF:

0.895

Gnomad NFE exome

AF:

0.958

Gnomad OTH exome

AF:

0.912

GnomAD4 exome

AF:

0.939

AC:

1368473

AN:

1457530

Hom.:

645943

Cov.:

AF XY:

0.939

AC XY:

680405

AN XY:

724938

show subpopulations

African (AFR)

AF:

0.902

AC:

29936

AN:

33204

American (AMR)

AF:

0.653

AC:

28874

AN:

44212

Ashkenazi Jewish (ASJ)

AF:

0.973

AC:

25233

AN:

25936

East Asian (EAS)

AF:

0.777

AC:

30672

AN:

39490

South Asian (SAS)

AF:

0.871

AC:

74473

AN:

85526

European-Finnish (FIN)

AF:

0.896

AC:

47760

AN:

53282

Middle Eastern (MID)

AF:

0.977

AC:

5610

AN:

5744

European-Non Finnish (NFE)

AF:

0.964

AC:

1069563

AN:

1109942

Other (OTH)

AF:

0.936

AC:

56352

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3612

7225

10837

14450

18062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21560

43120

64680

86240

107800

<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:

0.913

AC:

139001

AN:

152232

Hom.:

63882

Cov.:

AF XY:

0.906

AC XY:

67453

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.900

AC:

37391

AN:

41544

American (AMR)

AF:

0.778

AC:

11894

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.979

AC:

3396

AN:

3470

East Asian (EAS)

AF:

0.784

AC:

4059

AN:

5174

South Asian (SAS)

AF:

0.869

AC:

4189

AN:

4820

European-Finnish (FIN)

AF:

0.895

AC:

9474

AN:

10590

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.963

AC:

65527

AN:

68030

Other (OTH)

AF:

0.928

AC:

1963

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

567

1134

1700

2267

2834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.945

Hom.:

173122

Bravo

AF:

0.902

TwinsUK

AF:

0.958

AC:

3552

ALSPAC

AF:

0.966

AC:

3724

ESP6500AA

AF:

0.898

AC:

3430

ESP6500EA

AF:

0.963

AC:

7965

ExAC

AF:

0.888

AC:

107276

Asia WGS

AF:

0.832

AC:

2893

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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 -

Oct 05, 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. -

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:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2021

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

0.052

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.077

T;T

MetaRNN

Benign

6.1e-7

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.8

N;N

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.088

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.021

MPC

1.2

ClinPred

0.0090

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.23

Mutation Taster

=99/1

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