chr15-40016658-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.3916G>T(p.Gly1306Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,613,804 control chromosomes in the GnomAD database, including 22,431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1470 hom., cov: 32)

Exomes 𝑓: 0.16 ( 20961 hom. )

Consequence

EIF2AK4
NM_001013703.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.90

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 (MetaRNN=0.002770543).

BP6

Variant 15-40016658-G-T is Benign according to our data. Variant chr15-40016658-G-T is described in ClinVar as [Benign]. Clinvar id is 381182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-40016658-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4 link	c.3916G>T	p.Gly1306Cys	missense_variant	Exon 28 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.3916G>T	p.Gly1306Cys	missense_variant	Exon 28 of 39	2	NM_001013703.4	ENSP00000263791.5	Q9P2K8-1
EIF2AK4	ENST00000558629.5 link	n.2833G>T		non_coding_transcript_exon_variant	Exon 11 of 22	1
EIF2AK4	ENST00000560855.5 link	c.3247G>T	p.Gly1083Cys	missense_variant	Exon 23 of 34	5		ENSP00000453575.1	H0YME5
EIF2AK4	ENST00000558557.1 link	n.923-450G>T		intron_variant	Intron 6 of 16	2

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

18989

AN:

152078

Hom.:

1471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0470

Gnomad AMI

AF:

0.148

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00442

Gnomad SAS

AF:

0.0797

Gnomad FIN

AF:

0.161

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.130

GnomAD3 exomes

AF:

0.129

AC:

32266

AN:

249278

Hom.:

2603

AF XY:

0.132

AC XY:

17846

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.0793

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.00284

Gnomad SAS exome

AF:

0.0803

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.135

GnomAD4 exome

AF:

0.163

AC:

238386

AN:

1461608

Hom.:

20961

Cov.:

AF XY:

0.161

AC XY:

117323

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.0424

Gnomad4 AMR exome

AF:

0.0824

Gnomad4 ASJ exome

AF:

0.168

Gnomad4 EAS exome

AF:

0.00249

Gnomad4 SAS exome

AF:

0.0831

Gnomad4 FIN exome

AF:

0.162

Gnomad4 NFE exome

AF:

0.183

Gnomad4 OTH exome

AF:

0.145

GnomAD4 genome

AF:

0.125

AC:

18990

AN:

152196

Hom.:

1470

Cov.:

AF XY:

0.122

AC XY:

9105

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0470

Gnomad4 AMR

AF:

0.108

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.00443

Gnomad4 SAS

AF:

0.0797

Gnomad4 FIN

AF:

0.161

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.129

Alfa

AF:

0.156

Hom.:

3026

Bravo

AF:

0.118

TwinsUK

AF:

0.193

AC:

715

ALSPAC

AF:

0.188

AC:

723

ESP6500AA

AF:

0.0504

AC:

191

ESP6500EA

AF:

0.178

AC:

1463

ExAC

AF:

0.131

AC:

15765

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

EpiCase

AF:

0.171

EpiControl

AF:

0.170

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 11, 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. -

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 -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial pulmonary capillary hemangiomatosis

Benign:1

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.32

MPC

1.0

ClinPred

0.031

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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