15-39934294-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001013703.4(EIF2AK4):c.99T>C(p.Ile33Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,611,938 control chromosomes in the GnomAD database, including 627,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.91 ( 63084 hom., cov: 33)

Exomes 𝑓: 0.88 ( 564024 hom. )

Consequence

EIF2AK4
NM_001013703.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.310

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 15-39934294-T-C is Benign according to our data. Variant chr15-39934294-T-C is described in ClinVar as [Benign]. Clinvar id is 381178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39934294-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.31 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.99T>C	p.Ile33Ile	synonymous_variant	Exon 1 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.99T>C	p.Ile33Ile	synonymous_variant	Exon 1 of 39	2	NM_001013703.4	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000559624.5 link	c.99T>C	p.Ile33Ile	synonymous_variant	Exon 1 of 11	1		ENSP00000453148.1	Q9P2K8-3
EIF2AK4	ENST00000560648.1 link	c.99T>C	p.Ile33Ile	synonymous_variant	Exon 1 of 4	3		ENSP00000453968.1	H0YND8

Frequencies

GnomAD3 genomes

AF:

0.909

AC:

138230

AN:

152118

Hom.:

63018

Cov.:

show subpopulations

Gnomad AFR

AF:

0.975

Gnomad AMI

AF:

0.839

Gnomad AMR

AF:

0.896

Gnomad ASJ

AF:

0.912

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.983

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.920

Gnomad NFE

AF:

0.857

Gnomad OTH

AF:

0.901

GnomAD3 exomes

AF:

0.910

AC:

220106

AN:

241960

Hom.:

100464

AF XY:

0.909

AC XY:

120263

AN XY:

132234

show subpopulations

Gnomad AFR exome

AF:

0.977

Gnomad AMR exome

AF:

0.925

Gnomad ASJ exome

AF:

0.919

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.982

Gnomad FIN exome

AF:

0.926

Gnomad NFE exome

AF:

0.857

Gnomad OTH exome

AF:

0.904

GnomAD4 exome

AF:

0.878

AC:

1281702

AN:

1459702

Hom.:

564024

Cov.:

AF XY:

0.881

AC XY:

639509

AN XY:

726098

show subpopulations

Gnomad4 AFR exome

AF:

0.979

Gnomad4 AMR exome

AF:

0.922

Gnomad4 ASJ exome

AF:

0.914

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.981

Gnomad4 FIN exome

AF:

0.921

Gnomad4 NFE exome

AF:

0.857

Gnomad4 OTH exome

AF:

0.893

GnomAD4 genome

AF:

0.909

AC:

138355

AN:

152236

Hom.:

63084

Cov.:

AF XY:

0.913

AC XY:

67968

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.975

Gnomad4 AMR

AF:

0.896

Gnomad4 ASJ

AF:

0.912

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.983

Gnomad4 FIN

AF:

0.928

Gnomad4 NFE

AF:

0.857

Gnomad4 OTH

AF:

0.902

Alfa

AF:

0.870

Hom.:

72546

Bravo

AF:

0.909

Asia WGS

AF:

0.988

AC:

3437

AN:

3478

EpiCase

AF:

0.864

EpiControl

AF:

0.866

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

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 -

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

-0.62

CADD

Benign

DANN

Benign

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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