Variant 15-40003301-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5

The NM_001013703.4(EIF2AK4):c.3344C>T(p.Pro1115Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.71

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.93

PP5

Variant 15-40003301-C-T is Pathogenic according to our data. Variant chr15-40003301-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 426060.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 linkuse as main transcript	c.3344C>T	p.Pro1115Leu	missense_variant	23/39	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.3344C>T	p.Pro1115Leu	missense_variant	23/39	2	NM_001013703.4	ENSP00000263791	P1	Q9P2K8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249400

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Familial pulmonary capillary hemangiomatosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-9.7

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.73

Gain of sheet (P = 0.1945);

MVP

0.88

MPC

1.1

ClinPred

1.0

GERP RS

5.8

Varity_R

0.97

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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