rs2291627

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001013703.4(EIF2AK4):c.1321A>C(p.Ile441Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,614,002 control chromosomes in the GnomAD database, including 16,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2351 hom., cov: 31)

Exomes 𝑓: 0.11 ( 13852 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EIF2AK4. . Gene score misZ 2.6675 (greater than the threshold 3.09). Trascript score misZ 3.5194 (greater than threshold 3.09). GenCC has associacion of gene with pulmonary venoocclusive disease 2, pulmonary venoocclusive disease, heritable pulmonary arterial hypertension, pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis.

BP4

Computational evidence support a benign effect (MetaRNN=3.8290024E-4).

BP6

Variant 15-39967647-A-C is Benign according to our data. Variant chr15-39967647-A-C is described in ClinVar as [Benign]. Clinvar id is 381213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39967647-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 linkuse as main transcript	c.1321A>C	p.Ile441Leu	missense_variant	9/39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10 linkuse as main transcript	c.1321A>C	p.Ile441Leu	missense_variant	9/39	2	NM_001013703.4	ENSP00000263791	P1	Q9P2K8-1
EIF2AK4	ENST00000559624.5 linkuse as main transcript	c.1321A>C	p.Ile441Leu	missense_variant	9/11	1		ENSP00000453148		Q9P2K8-3
EIF2AK4	ENST00000560855.5 linkuse as main transcript	c.739A>C	p.Ile247Leu	missense_variant	5/34	5		ENSP00000453575

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22314

AN:

151994

Hom.:

2347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.128

Gnomad EAS

AF:

0.533

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.0980

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.0892

Gnomad OTH

AF:

0.148

GnomAD3 exomes

AF:

0.150

AC:

37441

AN:

249534

Hom.:

4640

AF XY:

0.149

AC XY:

20196

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.213

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.134

Gnomad EAS exome

AF:

0.545

Gnomad SAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.0968

Gnomad NFE exome

AF:

0.0881

Gnomad OTH exome

AF:

0.131

GnomAD4 exome

AF:

0.113

AC:

165434

AN:

1461890

Hom.:

13852

Cov.:

AF XY:

0.115

AC XY:

83509

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.220

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.130

Gnomad4 EAS exome

AF:

0.506

Gnomad4 SAS exome

AF:

0.184

Gnomad4 FIN exome

AF:

0.100

Gnomad4 NFE exome

AF:

0.0881

Gnomad4 OTH exome

AF:

0.144

GnomAD4 genome

AF:

0.147

AC:

22341

AN:

152112

Hom.:

2351

Cov.:

AF XY:

0.149

AC XY:

11063

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.124

Gnomad4 ASJ

AF:

0.128

Gnomad4 EAS

AF:

0.533

Gnomad4 SAS

AF:

0.201

Gnomad4 FIN

AF:

0.0980

Gnomad4 NFE

AF:

0.0893

Gnomad4 OTH

AF:

0.151

Alfa

AF:

0.110

Hom.:

3298

Bravo

AF:

0.152

TwinsUK

AF:

0.0885

AC:

328

ALSPAC

AF:

0.0913

AC:

352

ESP6500AA

AF:

0.191

AC:

762

ESP6500EA

AF:

0.0885

AC:

739

ExAC

AF:

0.149

AC:

18011

Asia WGS

AF:

0.349

AC:

1210

AN:

3478

EpiCase

AF:

0.0998

EpiControl

AF:

0.0981

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial pulmonary capillary hemangiomatosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.063

.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

D;T

MetaRNN

Benign

0.00038

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.63

N;N

MutationTaster

Benign

0.76

P;P;P

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.010

N;N

REVEL

Benign

0.075

Sift

Benign

1.0

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.0020

B;B

Vest4

0.11

MPC

0.23

ClinPred

0.0085

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.048

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over