rs34298786

chr15-39976851-G-Achr15-39976851-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:5
• Conservation: PhyloP100: 2.41

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]

ACMG classification

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	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	c.2249+7G>A		splice_region_variant, intron_variant		2	NM_001013703.4	P1
EIF2AK4	ENST00000560855.5	c.1665+7G>A		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52408 AN: 152002 Hom.: 9115 Cov.: 34

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

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.: 43 AF XY: 0.343 AC XY: 226229 AN XY: 660440

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.: 34 AF XY: 0.342 AC XY: 25462 AN XY: 74368

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:5

Revision: criteria provided, multiple submitters, no conflicts

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. -

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	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Other links and lift over

dbSNP: rs34298786; hg19: chr15-40269052; COSMIC: COSV55464750; COSMIC: COSV55464750;