rs34298786

Positions:

Variant summary

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

The NM_001013703.4(EIF2AK4):c.2249+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,497,880 control chromosomes in the GnomAD database, including 89,125 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 0.34 ( 9117 hom., cov: 34)

Exomes 𝑓: 0.34 ( 80008 hom. )

Consequence

EIF2AK4
NM_001013703.4 splice_region, intron

Scores

Splicing: ADA: 0.0004469

Clinical Significance

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

Conservation

PhyloP100: 2.41

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=-0.75).

BP6

Variant 15-39976851-G-A is Benign according to our data. Variant chr15-39976851-G-A is described in ClinVar as [Benign]. Clinvar id is 381180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39976851-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4 linkuse as main transcript	c.2249+7G>A		splice_region_variant, intron_variant		ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10 linkuse as main transcript	c.2249+7G>A		splice_region_variant, intron_variant		2	NM_001013703.4	P1	Q9P2K8-1
EIF2AK4	ENST00000560855.5 linkuse as main transcript	c.1665+7G>A		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52408

AN:

152002

Hom.:

9115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.181

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.324

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.356

Gnomad OTH

AF:

0.371

GnomAD3 exomes

AF:

0.326

AC:

48484

AN:

148540

Hom.:

8274

AF XY:

0.331

AC XY:

27301

AN XY:

82434

show subpopulations

Gnomad AFR exome

AF:

0.356

Gnomad AMR exome

AF:

0.274

Gnomad ASJ exome

AF:

0.365

Gnomad EAS exome

AF:

0.163

Gnomad SAS exome

AF:

0.328

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.357

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.342

AC:

460702

AN:

1345760

Hom.:

80008

Cov.:

AF XY:

0.343

AC XY:

226229

AN XY:

660440

show subpopulations

Gnomad4 AFR exome

AF:

0.359

Gnomad4 AMR exome

AF:

0.276

Gnomad4 ASJ exome

AF:

0.374

Gnomad4 EAS exome

AF:

0.204

Gnomad4 SAS exome

AF:

0.327

Gnomad4 FIN exome

AF:

0.317

Gnomad4 NFE exome

AF:

0.349

Gnomad4 OTH exome

AF:

0.344

GnomAD4 genome

AF:

0.345

AC:

52423

AN:

152120

Hom.:

9117

Cov.:

AF XY:

0.342

AC XY:

25462

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.358

Gnomad4 AMR

AF:

0.329

Gnomad4 ASJ

AF:

0.364

Gnomad4 EAS

AF:

0.180

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.324

Gnomad4 NFE

AF:

0.356

Gnomad4 OTH

AF:

0.366

Alfa

AF:

0.254

Hom.:

959

Bravo

AF:

0.347

Asia WGS

AF:

0.247

AC:

859

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2016	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial pulmonary capillary hemangiomatosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.0

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00045

dbscSNV1_RF

Benign

0.040

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