15-39973598-A-G

Position:

chr15-39973598-A-G

Variant summary

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

The NM_001013703.4(EIF2AK4):c.1667A>G(p.Glu556Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.936 in 1,609,762 control chromosomes in the GnomAD database, including 709,825 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 0.91 ( 63882 hom., cov: 31)

Exomes 𝑓: 0.94 ( 645943 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.53

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=6.1075446E-7).

BP6

Variant 15-39973598-A-G is Benign according to our data. Variant chr15-39973598-A-G is described in ClinVar as [Benign]. Clinvar id is 381179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39973598-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4 linkuse as main transcript	c.1667A>G	p.Glu556Gly	missense_variant	11/39	ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10 linkuse as main transcript	c.1667A>G	p.Glu556Gly	missense_variant	11/39	2	NM_001013703.4	P1	Q9P2K8-1
EIF2AK4	ENST00000559624.5 linkuse as main transcript	c.1667A>G	p.Glu556Gly	missense_variant	11/11	1			Q9P2K8-3
EIF2AK4	ENST00000560855.5 linkuse as main transcript	c.1085A>G	p.Glu362Gly	missense_variant	7/34	5

Frequencies

GnomAD3 genomes

AF:

0.913

AC:

138918

AN:

152114

Hom.:

63848

Cov.:

show subpopulations

Gnomad AFR

AF:

0.900

Gnomad AMI

AF:

0.904

Gnomad AMR

AF:

0.779

Gnomad ASJ

AF:

0.979

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.869

Gnomad FIN

AF:

0.895

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.963

Gnomad OTH

AF:

0.927

GnomAD3 exomes

AF:

0.880

AC:

216504

AN:

245890

Hom.:

97149

AF XY:

0.891

AC XY:

118881

AN XY:

133388

show subpopulations

Gnomad AFR exome

AF:

0.899

Gnomad AMR exome

AF:

0.636

Gnomad ASJ exome

AF:

0.973

Gnomad EAS exome

AF:

0.785

Gnomad SAS exome

AF:

0.865

Gnomad FIN exome

AF:

0.895

Gnomad NFE exome

AF:

0.958

Gnomad OTH exome

AF:

0.912

GnomAD4 exome

AF:

0.939

AC:

1368473

AN:

1457530

Hom.:

645943

Cov.:

AF XY:

0.939

AC XY:

680405

AN XY:

724938

show subpopulations

Gnomad4 AFR exome

AF:

0.902

Gnomad4 AMR exome

AF:

0.653

Gnomad4 ASJ exome

AF:

0.973

Gnomad4 EAS exome

AF:

0.777

Gnomad4 SAS exome

AF:

0.871

Gnomad4 FIN exome

AF:

0.896

Gnomad4 NFE exome

AF:

0.964

Gnomad4 OTH exome

AF:

0.936

GnomAD4 genome

AF:

0.913

AC:

139001

AN:

152232

Hom.:

63882

Cov.:

AF XY:

0.906

AC XY:

67453

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.900

Gnomad4 AMR

AF:

0.778

Gnomad4 ASJ

AF:

0.979

Gnomad4 EAS

AF:

0.784

Gnomad4 SAS

AF:

0.869

Gnomad4 FIN

AF:

0.895

Gnomad4 NFE

AF:

0.963

Gnomad4 OTH

AF:

0.928

Alfa

AF:

0.951

Hom.:

128925

Bravo

AF:

0.902

TwinsUK

AF:

0.958

AC:

3552

ALSPAC

AF:

0.966

AC:

3724

ESP6500AA

AF:

0.898

AC:

3430

ESP6500EA

AF:

0.963

AC:

7965

ExAC

AF:

0.888

AC:

107276

Asia WGS

AF:

0.832

AC:

2893

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

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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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. -

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:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.077

T;T

MetaRNN

Benign

6.1e-7

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.8

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.050

N;N

REVEL

Benign

0.088

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.021

MPC

1.2

ClinPred

0.0090

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.23

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