rs2412459

Positions:

• chr15-40003758-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001013703.4(EIF2AK4):​c.3357+444C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.877 in 152,256 control chromosomes in the GnomAD database, including 58,947 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.88 (58947 hom., cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.644

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.3357+444C>T		intron_variant		ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.3357+444C>T		intron_variant		2	NM_001013703.4	P1

Frequencies

GnomAD3 genomes AF: 0.877 AC: 133377 AN: 152138 Hom.: 58912 Cov.: 33

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.892

Gnomad ASJ AF: 0.896

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.904

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.886

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.877 AC: 133465 AN: 152256 Hom.: 58947 Cov.: 33 AF XY: 0.875 AC XY: 65100 AN XY: 74442

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.892

Gnomad4 ASJ AF: 0.896

Gnomad4 EAS AF: 0.544

Gnomad4 SAS AF: 0.893

Gnomad4 FIN AF: 0.904

Gnomad4 NFE AF: 0.920

Gnomad4 OTH AF: 0.885

Alfa AF: 0.910 Hom.: 80258

Bravo AF: 0.871

Asia WGS AF: 0.754 AC: 2625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2412459; hg19: chr15-40295959;