15-40003758-C-T

Variant names:

• chr15-40003758-C-T
• rs2412459
• NM_001013703.4:c.3357+444C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary venoocclusive disease 2

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulmonary venoocclusive disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306490 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013703.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	NM_001013703.4	MANE Select	c.3357+444C>T		intron	N/A	NP_001013725.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.3357+444C>T		intron	N/A	ENSP00000263791.5
	EIF2AK4	ENST00000558629.5	TSL:1	n.2274+444C>T		intron	N/A
	EIF2AK4	ENST00000560855.5	TSL:5	c.2688+444C>T		intron	N/A	ENSP00000453575.1

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

African (AFR) AF: 0.830 AC: 34453 AN: 41526

American (AMR) AF: 0.892 AC: 13645 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.896 AC: 3111 AN: 3472

East Asian (EAS) AF: 0.544 AC: 2812 AN: 5170

South Asian (SAS) AF: 0.893 AC: 4315 AN: 4832

European-Finnish (FIN) AF: 0.904 AC: 9590 AN: 10610

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.920 AC: 62581 AN: 68024

Other (OTH) AF: 0.885 AC: 1870 AN: 2112

Alfa AF: 0.900 Hom.: 193064

Bravo AF: 0.871

Asia WGS AF: 0.754 AC: 2625 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.56
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2412459; hg19: chr15-40295959;