Genetic Variant NM_001013703.4:c.1667A>C (chr15-39973598-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001013703.4(EIF2AK4):c.1667A>C(p.Glu556Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E556G) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.53

Publications

36 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06759575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.1667A>C	p.Glu556Ala	missense_variant	Exon 11 of 39	ENST00000263791.10	NP_001013725.2	Q9P2K8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF2AK4	ENST00000263791.10 link	c.1667A>C	p.Glu556Ala	missense_variant	Exon 11 of 39	2	NM_001013703.4	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000559624.5 link	c.1667A>C	p.Glu556Ala	missense_variant	Exon 11 of 11	1		ENSP00000453148.1	Q9P2K8-3
EIF2AK4	ENST00000560855.5 link	c.1082A>C	p.Glu361Ala	missense_variant	Exon 7 of 34	5		ENSP00000453575.1	H0YME5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1457726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725064

African (AFR)

AF:

0.00

AC:

AN:

33210

American (AMR)

AF:

0.00

AC:

AN:

44240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25936

East Asian (EAS)

AF:

0.00

AC:

AN:

39508

South Asian (SAS)

AF:

0.00

AC:

AN:

85580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110020

Other (OTH)

AF:

0.00

AC:

AN:

60200

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.048

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.18

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.55

N;N

PhyloP100

2.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.076

Sift

Benign

0.66

T;T

Sift4G

Benign

0.85

T;T

Polyphen

0.0

B;B

Vest4

0.030

MutPred

0.26

Loss of disorder (P = 0.0764);Loss of disorder (P = 0.0764);

MVP

0.77

MPC

1.1

ClinPred

0.33

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over