15-40030351-G-T

Variant names:

• chr15-40030351-G-T
• rs2250402
• NM_001013703.4:c.4562-8G>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.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

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=-0.7).
• 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	c.4562-8G>T		splice_region_variant, intron_variant	Intron 34 of 38	ENST00000263791.10	NP_001013725.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140380 AN: 152084 Hom.: 64865 Cov.: 30

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

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.: 38 AF XY: 0.915 AC XY: 664911 AN XY: 726834

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.: 30 AF XY: 0.920 AC XY: 68479 AN XY: 74400

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

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	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -

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 27, 2024	- -

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

Other links and lift over

dbSNP: rs2250402; hg19: chr15-40322552; COSMIC: COSV55472359; COSMIC: COSV55472359;