rs3207297

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001013703.4(EIF2AK4):c.4215C>T(p.Gly1405Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,611,428 control chromosomes in the GnomAD database, including 101,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9232 hom., cov: 31)

Exomes 𝑓: 0.35 ( 91888 hom. )

Consequence

EIF2AK4
NM_001013703.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0170

Publications

13 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 15-40020940-C-T is Benign according to our data. Variant chr15-40020940-C-T is described in ClinVar as [Benign]. Clinvar id is 381184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.017 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.4215C>T	p.Gly1405Gly	synonymous_variant	Exon 31 of 39	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.4215C>T	p.Gly1405Gly	synonymous_variant	Exon 31 of 39	2	NM_001013703.4	ENSP00000263791.5		Q9P2K8-1

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

52926

AN:

151696

Hom.:

9225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.340

Gnomad AMI

AF:

0.466

Gnomad AMR

AF:

0.327

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.255

Gnomad SAS

AF:

0.362

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.381

GnomAD2 exomes

AF:

0.341

AC:

84664

AN:

248142

AF XY:

0.346

show subpopulations

Gnomad AFR exome

AF:

0.340

Gnomad AMR exome

AF:

0.283

Gnomad ASJ exome

AF:

0.366

Gnomad EAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.330

Gnomad NFE exome

AF:

0.364

Gnomad OTH exome

AF:

0.364

GnomAD4 exome

AF:

0.353

AC:

515927

AN:

1459612

Hom.:

91888

Cov.:

AF XY:

0.355

AC XY:

257867

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.337

AC:

11276

AN:

33414

American (AMR)

AF:

0.290

AC:

12899

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9795

AN:

26086

East Asian (EAS)

AF:

0.285

AC:

11279

AN:

39638

South Asian (SAS)

AF:

0.380

AC:

32628

AN:

85880

European-Finnish (FIN)

AF:

0.331

AC:

17652

AN:

53368

Middle Eastern (MID)

AF:

0.414

AC:

2345

AN:

5666

European-Non Finnish (NFE)

AF:

0.357

AC:

396457

AN:

1110740

Other (OTH)

AF:

0.358

AC:

21596

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

16141

32283

48424

64566

80707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.349

AC:

52951

AN:

151816

Hom.:

9232

Cov.:

AF XY:

0.347

AC XY:

25758

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.340

AC:

14055

AN:

41360

American (AMR)

AF:

0.328

AC:

4997

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

1268

AN:

3466

East Asian (EAS)

AF:

0.254

AC:

1306

AN:

5138

South Asian (SAS)

AF:

0.362

AC:

1744

AN:

4812

European-Finnish (FIN)

AF:

0.331

AC:

3491

AN:

10548

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.364

AC:

24758

AN:

67930

Other (OTH)

AF:

0.376

AC:

792

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1748

3495

5243

6990

8738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.361

Hom.:

45293

Bravo

AF:

0.348

Asia WGS

AF:

0.294

AC:

1025

AN:

3478

EpiCase

AF:

0.378

EpiControl

AF:

0.375

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

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

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

-0.28

CADD

Benign

9.8

(source)

DANN

Benign

0.69

PhyloP100

-0.017

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=83/17

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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rs3207297

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