15-40008013-G-C

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.3408-14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,501,930 control chromosomes in the GnomAD database, including 107,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10106 hom., cov: 32)

Exomes 𝑓: 0.38 ( 97560 hom. )

Consequence

EIF2AK4
NM_001013703.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.41

Publications

11 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 (BayesDel_noAF=-0.62).

BP6

Variant 15-40008013-G-C is Benign according to our data. Variant chr15-40008013-G-C is described in ClinVar as Benign. ClinVar VariationId is 381181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.3408-14G>C		intron_variant	Intron 24 of 38	ENST00000263791.10	NP_001013725.2	Q9P2K8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10 link	c.3408-14G>C		intron_variant	Intron 24 of 38	2	NM_001013703.4	ENSP00000263791.5		Q9P2K8-1

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

54827

AN:

151762

Hom.:

10090

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.291

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.347

Gnomad EAS

AF:

0.292

Gnomad SAS

AF:

0.454

Gnomad FIN

AF:

0.412

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.343

GnomAD2 exomes

AF:

0.391

AC:

70895

AN:

181496

AF XY:

0.391

show subpopulations

Gnomad AFR exome

AF:

0.302

Gnomad AMR exome

AF:

0.527

Gnomad ASJ exome

AF:

0.340

Gnomad EAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.417

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.389

GnomAD4 exome

AF:

0.377

AC:

508320

AN:

1350050

Hom.:

97560

Cov.:

AF XY:

0.378

AC XY:

251265

AN XY:

664434

show subpopulations

African (AFR)

AF:

0.300

AC:

8671

AN:

28914

American (AMR)

AF:

0.507

AC:

14007

AN:

27636

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

7409

AN:

21890

East Asian (EAS)

AF:

0.269

AC:

9415

AN:

35000

South Asian (SAS)

AF:

0.442

AC:

30487

AN:

68926

European-Finnish (FIN)

AF:

0.411

AC:

20895

AN:

50900

Middle Eastern (MID)

AF:

0.359

AC:

1920

AN:

5346

European-Non Finnish (NFE)

AF:

0.374

AC:

395177

AN:

1056082

Other (OTH)

AF:

0.367

AC:

20339

AN:

55356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

14801

29602

44402

59203

74004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12986

25972

38958

51944

64930

<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:

0.361

AC:

54865

AN:

151880

Hom.:

10106

Cov.:

AF XY:

0.364

AC XY:

27043

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.306

AC:

12660

AN:

41386

American (AMR)

AF:

0.427

AC:

6522

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

1201

AN:

3464

East Asian (EAS)

AF:

0.293

AC:

1513

AN:

5172

South Asian (SAS)

AF:

0.453

AC:

2183

AN:

4814

European-Finnish (FIN)

AF:

0.412

AC:

4339

AN:

10538

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.373

AC:

25338

AN:

67936

Other (OTH)

AF:

0.347

AC:

731

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1805

3610

5415

7220

9025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

550

1100

1650

2200

2750

<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:

0.359

Hom.:

1868

Bravo

AF:

0.357

Asia WGS

AF:

0.402

AC:

1397

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 11, 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

Feb 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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