rs35602605

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.3916G>T(p.Gly1306Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,804 control chromosomes in the GnomAD database, including 22,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1470 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20961 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.90

Publications

27 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:

ENSG00000306490 (HGNC:):

ENSG00000306490 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=0.002770543).

BP6

Variant 15-40016658-G-T is Benign according to our data. Variant chr15-40016658-G-T is described in ClinVar as Benign. ClinVar VariationId is 381182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013703.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	NM_001013703.4	MANE Select	c.3916G>T	p.Gly1306Cys	missense	Exon 28 of 39	NP_001013725.2	Q9P2K8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.3916G>T	p.Gly1306Cys	missense	Exon 28 of 39	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000558629.5	TSL:1	n.2833G>T		non_coding_transcript_exon	Exon 11 of 22
EIF2AK4	ENST00000917949.1		c.3958G>T	p.Gly1320Cys	missense	Exon 29 of 40	ENSP00000588008.1

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

18989

AN:

152078

Hom.:

1471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0470

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0797

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.129

AC:

32266

AN:

249278

AF XY:

0.132

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.0793

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.00284

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.163

AC:

238386

AN:

1461608

Hom.:

20961

Cov.:

AF XY:

0.161

AC XY:

117323

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.0424

AC:

1420

AN:

33456

American (AMR)

AF:

0.0824

AC:

3683

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4394

AN:

26132

East Asian (EAS)

AF:

0.00249

AC:

AN:

39696

South Asian (SAS)

AF:

0.0831

AC:

7160

AN:

86198

European-Finnish (FIN)

AF:

0.162

AC:

8668

AN:

53400

Middle Eastern (MID)

AF:

0.130

AC:

750

AN:

5766

European-Non Finnish (NFE)

AF:

0.183

AC:

203465

AN:

1111878

Other (OTH)

AF:

0.145

AC:

8747

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

10280

20561

30841

41122

51402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7014

14028

21042

28056

35070

<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:

0.125

AC:

18990

AN:

152196

Hom.:

1470

Cov.:

AF XY:

0.122

AC XY:

9105

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0470

AC:

1952

AN:

41532

American (AMR)

AF:

0.108

AC:

1652

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

627

AN:

3472

East Asian (EAS)

AF:

0.00443

AC:

AN:

5194

South Asian (SAS)

AF:

0.0797

AC:

384

AN:

4816

European-Finnish (FIN)

AF:

0.161

AC:

1702

AN:

10568

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.180

AC:

12212

AN:

68004

Other (OTH)

AF:

0.129

AC:

272

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

865

1730

2595

3460

4325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

206

412

618

824

1030

<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:

0.153

Hom.:

6749

Bravo

AF:

0.118

TwinsUK

AF:

0.193

AC:

715

ALSPAC

AF:

0.188

AC:

723

ESP6500AA

AF:

0.0504

AC:

191

ESP6500EA

AF:

0.178

AC:

1463

ExAC

AF:

0.131

AC:

15765

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

EpiCase

AF:

0.171

EpiControl

AF:

0.170

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Familial pulmonary capillary hemangiomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.32

MPC

1.0

ClinPred

0.031

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.81

Mutation Taster

=41/59

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over