rs566792

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001013703.4(EIF2AK4):c.99T>C(p.Ile33Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,611,938 control chromosomes in the GnomAD database, including 627,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.91 ( 63084 hom., cov: 33)

Exomes 𝑓: 0.88 ( 564024 hom. )

Consequence

EIF2AK4
NM_001013703.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.310

Publications

23 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: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
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

new If you want to explore the variant's impact on the transcript NM_001013703.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 15-39934294-T-C is Benign according to our data. Variant chr15-39934294-T-C is described in ClinVar as Benign. ClinVar VariationId is 381178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.99T>C	p.Ile33Ile	synonymous	Exon 1 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.99T>C	p.Ile33Ile	synonymous	Exon 1 of 39	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000559624.5	TSL:1	c.99T>C	p.Ile33Ile	synonymous	Exon 1 of 11	ENSP00000453148.1	Q9P2K8-3
EIF2AK4	ENST00000917949.1		c.99T>C	p.Ile33Ile	synonymous	Exon 1 of 40	ENSP00000588008.1

Frequencies

GnomAD3 genomes

AF:

0.909

AC:

138230

AN:

152118

Hom.:

63018

Cov.:

show subpopulations

Gnomad AFR

AF:

0.975

Gnomad AMI

AF:

0.839

Gnomad AMR

AF:

0.896

Gnomad ASJ

AF:

0.912

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.983

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.920

Gnomad NFE

AF:

0.857

Gnomad OTH

AF:

0.901

GnomAD2 exomes

AF:

0.910

AC:

220106

AN:

241960

AF XY:

0.909

show subpopulations

Gnomad AFR exome

AF:

0.977

Gnomad AMR exome

AF:

0.925

Gnomad ASJ exome

AF:

0.919

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.926

Gnomad NFE exome

AF:

0.857

Gnomad OTH exome

AF:

0.904

GnomAD4 exome

AF:

0.878

AC:

1281702

AN:

1459702

Hom.:

564024

Cov.:

AF XY:

0.881

AC XY:

639509

AN XY:

726098

show subpopulations

African (AFR)

AF:

0.979

AC:

32699

AN:

33408

American (AMR)

AF:

0.922

AC:

41107

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

23803

AN:

26032

East Asian (EAS)

AF:

1.00

AC:

39660

AN:

39664

South Asian (SAS)

AF:

0.981

AC:

84319

AN:

85922

European-Finnish (FIN)

AF:

0.921

AC:

48844

AN:

53030

Middle Eastern (MID)

AF:

0.941

AC:

5423

AN:

5760

European-Non Finnish (NFE)

AF:

0.857

AC:

952038

AN:

1111050

Other (OTH)

AF:

0.893

AC:

53809

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

9210

18420

27630

36840

46050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21252

42504

63756

85008

106260

<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:

0.909

AC:

138355

AN:

152236

Hom.:

63084

Cov.:

AF XY:

0.913

AC XY:

67968

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.975

AC:

40544

AN:

41580

American (AMR)

AF:

0.896

AC:

13718

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.912

AC:

3166

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5169

AN:

5170

South Asian (SAS)

AF:

0.983

AC:

4752

AN:

4832

European-Finnish (FIN)

AF:

0.928

AC:

9839

AN:

10602

Middle Eastern (MID)

AF:

0.914

AC:

267

AN:

292

European-Non Finnish (NFE)

AF:

0.857

AC:

58233

AN:

67960

Other (OTH)

AF:

0.902

AC:

1905

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

641

1282

1922

2563

3204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.876

Hom.:

99295

Bravo

AF:

0.909

Asia WGS

AF:

0.988

AC:

3437

AN:

3478

EpiCase

AF:

0.864

EpiControl

AF:

0.866

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial pulmonary capillary hemangiomatosis (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.31

PromoterAI

-0.0020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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