15-40030351-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001013703.4(EIF2AK4):c.4562-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.916 in 1,613,276 control chromosomes in the GnomAD database, including 677,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.92 ( 64902 hom., cov: 30)

Exomes 𝑓: 0.92 ( 612869 hom. )

Consequence

EIF2AK4
NM_001013703.4 splice_region, intron

Scores

Splicing: ADA: 0.00001672

Clinical Significance

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

Conservation

PhyloP100: 0.269

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 15-40030351-G-T is Benign according to our data. Variant chr15-40030351-G-T is described in ClinVar as [Benign]. Clinvar id is 381185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40030351-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.4562-8G>T		splice_region_variant, intron_variant	Intron 34 of 38	ENST00000263791.10	NP_001013725.2	Q9P2K8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10 link	c.4562-8G>T		splice_region_variant, intron_variant	Intron 34 of 38	2	NM_001013703.4	ENSP00000263791.5		Q9P2K8-1

Frequencies

GnomAD3 genomes

AF:

0.923

AC:

140380

AN:

152084

Hom.:

64865

Cov.:

show subpopulations

Gnomad AFR

AF:

0.943

Gnomad AMI

AF:

0.949

Gnomad AMR

AF:

0.947

Gnomad ASJ

AF:

0.900

Gnomad EAS

AF:

0.780

Gnomad SAS

AF:

0.907

Gnomad FIN

AF:

0.899

Gnomad MID

AF:

0.918

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.930

GnomAD3 exomes

AF:

0.914

AC:

226881

AN:

248362

Hom.:

103914

AF XY:

0.912

AC XY:

122956

AN XY:

134784

show subpopulations

Gnomad AFR exome

AF:

0.941

Gnomad AMR exome

AF:

0.966

Gnomad ASJ exome

AF:

0.900

Gnomad EAS exome

AF:

0.768

Gnomad SAS exome

AF:

0.906

Gnomad FIN exome

AF:

0.905

Gnomad NFE exome

AF:

0.921

Gnomad OTH exome

AF:

0.917

GnomAD4 exome

AF:

0.915

AC:

1337545

AN:

1461074

Hom.:

612869

Cov.:

AF XY:

0.915

AC XY:

664911

AN XY:

726834

show subpopulations

Gnomad4 AFR exome

AF:

0.941

Gnomad4 AMR exome

AF:

0.963

Gnomad4 ASJ exome

AF:

0.897

Gnomad4 EAS exome

AF:

0.772

Gnomad4 SAS exome

AF:

0.904

Gnomad4 FIN exome

AF:

0.905

Gnomad4 NFE exome

AF:

0.920

Gnomad4 OTH exome

AF:

0.905

GnomAD4 genome

AF:

0.923

AC:

140473

AN:

152202

Hom.:

64902

Cov.:

AF XY:

0.920

AC XY:

68479

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.942

Gnomad4 AMR

AF:

0.947

Gnomad4 ASJ

AF:

0.900

Gnomad4 EAS

AF:

0.779

Gnomad4 SAS

AF:

0.907

Gnomad4 FIN

AF:

0.899

Gnomad4 NFE

AF:

0.922

Gnomad4 OTH

AF:

0.931

Alfa

AF:

0.921

Hom.:

103768

Bravo

AF:

0.927

EpiCase

AF:

0.919

EpiControl

AF:

0.920

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -

Oct 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial pulmonary capillary hemangiomatosis

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

5.7

DANN

Benign

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0

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