Variant 15-39939532-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001013703.4(EIF2AK4):c.172G>C(p.Val58Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,457,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

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 Uncertain_significance. Variant got 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.17961815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 linkuse as main transcript	c.172G>C	p.Val58Leu	missense_variant	2/39	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.172G>C	p.Val58Leu	missense_variant	2/39	2	NM_001013703.4	ENSP00000263791	P1	Q9P2K8-1
EIF2AK4	ENST00000559624.5 linkuse as main transcript	c.172G>C	p.Val58Leu	missense_variant	2/11	1		ENSP00000453148		Q9P2K8-3
EIF2AK4	ENST00000560648.1 linkuse as main transcript	c.172G>C	p.Val58Leu	missense_variant	2/4	3		ENSP00000453968

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248176

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.172G>C (p.V58L) alteration is located in exon 2 (coding exon 2) of the EIF2AK4 gene. This alteration results from a G to C substitution at nucleotide position 172, causing the valine (V) at amino acid position 58 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.051

.;T;T

Eigen

Benign

-0.078

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.0055

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.

MutationTaster

Benign

0.77

N;N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.68

N;N;N

REVEL

Benign

0.042

Sift

Benign

0.23

T;T;T

Sift4G

Benign

0.074

T;T;D

Polyphen

0.0070

B;B;.

Vest4

0.35

MutPred

0.44

Gain of catalytic residue at V58 (P = 0.0981);Gain of catalytic residue at V58 (P = 0.0981);Gain of catalytic residue at V58 (P = 0.0981);

MVP

0.67

MPC

0.44

ClinPred

0.56

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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