rs34298786

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.2249+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,497,880 control chromosomes in the GnomAD database, including 89,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9117 hom., cov: 34)

Exomes 𝑓: 0.34 ( 80008 hom. )

Consequence

EIF2AK4
NM_001013703.4 splice_region, intron

Scores

Splicing: ADA: 0.0004469

Clinical Significance

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

Conservation

PhyloP100: 2.41

Publications

8 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 (BayesDel_noAF=-0.75).

BP6

Variant 15-39976851-G-A is Benign according to our data. Variant chr15-39976851-G-A is described in ClinVar as [Benign]. Clinvar id is 381180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.2249+7G>A		splice_region_variant, intron_variant	Intron 12 of 38	ENST00000263791.10	NP_001013725.2	Q9P2K8-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF2AK4	ENST00000263791.10 link	c.2249+7G>A	splice_region_variant, intron_variant	Intron 12 of 38	2	NM_001013703.4	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000560855.5 link	c.1664+7G>A	splice_region_variant, intron_variant	Intron 8 of 33	5		ENSP00000453575.1	H0YME5
EIF2AK4	ENST00000624709.1 link	n.-128G>A	upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52408

AN:

152002

Hom.:

9115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.356

Gnomad OTH

AF:

0.371

GnomAD2 exomes

AF:

0.326

AC:

48484

AN:

148540

AF XY:

0.331

show subpopulations

Gnomad AFR exome

AF:

0.356

Gnomad AMR exome

AF:

0.274

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.163

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.342

AC:

460702

AN:

1345760

Hom.:

80008

Cov.:

AF XY:

0.343

AC XY:

226229

AN XY:

660440

show subpopulations

African (AFR)

AF:

0.359

AC:

9783

AN:

27254

American (AMR)

AF:

0.276

AC:

7766

AN:

28122

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

7568

AN:

20252

East Asian (EAS)

AF:

0.204

AC:

6989

AN:

34178

South Asian (SAS)

AF:

0.327

AC:

23056

AN:

70560

European-Finnish (FIN)

AF:

0.317

AC:

14702

AN:

46448

Middle Eastern (MID)

AF:

0.384

AC:

2040

AN:

5314

European-Non Finnish (NFE)

AF:

0.349

AC:

369697

AN:

1058110

Other (OTH)

AF:

0.344

AC:

19101

AN:

55522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17207

34414

51620

68827

86034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.345

AC:

52423

AN:

152120

Hom.:

9117

Cov.:

AF XY:

0.342

AC XY:

25462

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.358

AC:

14862

AN:

41494

American (AMR)

AF:

0.329

AC:

5037

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1263

AN:

3470

East Asian (EAS)

AF:

0.180

AC:

931

AN:

5172

South Asian (SAS)

AF:

0.300

AC:

1446

AN:

4820

European-Finnish (FIN)

AF:

0.324

AC:

3426

AN:

10578

Middle Eastern (MID)

AF:

0.360

AC:

105

AN:

292

European-Non Finnish (NFE)

AF:

0.356

AC:

24187

AN:

67972

Other (OTH)

AF:

0.366

AC:

772

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1691

3382

5074

6765

8456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.254

Hom.:

959

Bravo

AF:

0.347

Asia WGS

AF:

0.247

AC:

859

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

Nov 03, 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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial pulmonary capillary hemangiomatosis

Benign:2

Nov 13, 2024

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

-0.75

CADD

Benign

6.0

(source)

DANN

Benign

0.93

PhyloP100

2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00045

dbscSNV1_RF

Benign

0.040

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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rs34298786

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