15-40029923-T-C

Variant names:

• chr15-40029923-T-C
• rs937213
• NM_001013703.4:c.4562-436T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001013703.4(EIF2AK4):​c.4562-436T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 152,152 control chromosomes in the GnomAD database, including 8,870 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 0.31 (8870 hom., cov: 32)
• Consequence: EIF2AK4 NM_001013703.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.242
• Publications: 28 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.4562-436T>C		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.4562-436T>C		intron_variant	Intron 34 of 38	2	NM_001013703.4	ENSP00000263791.5
EIF2AK4	ENST00000558629.5	n.3479-436T>C		intron_variant	Intron 17 of 21	1
EIF2AK4	ENST00000560855.5	c.3893-436T>C		intron_variant	Intron 29 of 33	5		ENSP00000453575.1
EIF2AK4	ENST00000558557.1	n.1554-436T>C		intron_variant	Intron 12 of 16	2

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46772 AN: 152034 Hom.: 8873 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.307 AC: 46769 AN: 152152 Hom.: 8870 Cov.: 32 AF XY: 0.309 AC XY: 22962 AN XY: 74366

African (AFR) AF: 0.121 AC: 5042 AN: 41558

American (AMR) AF: 0.254 AC: 3888 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1541 AN: 3466

East Asian (EAS) AF: 0.0121 AC: 63 AN: 5186

South Asian (SAS) AF: 0.345 AC: 1662 AN: 4822

European-Finnish (FIN) AF: 0.464 AC: 4895 AN: 10558

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.421 AC: 28617 AN: 67962

Other (OTH) AF: 0.317 AC: 666 AN: 2100

Alfa AF: 0.388 Hom.: 23746

Bravo AF: 0.276

Asia WGS AF: 0.186 AC: 648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.81
PhyloP100		-0.24
PromoterAI		0.028	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs937213; hg19: chr15-40322124;