15-39934310-C-G

Variant names:

• chr15-39934310-C-G
• rs771007706
• NM_001013703.4:c.115C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013703.4(EIF2AK4):​c.115C>G​(p.Gln39Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15488464).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	NM_001013703.4	MANE Select	c.115C>G	p.Gln39Glu	missense	Exon 1 of 39	NP_001013725.2	Q9P2K8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.115C>G	p.Gln39Glu	missense	Exon 1 of 39	ENSP00000263791.5	Q9P2K8-1
	EIF2AK4	ENST00000559624.5	TSL:1	c.115C>G	p.Gln39Glu	missense	Exon 1 of 11	ENSP00000453148.1	Q9P2K8-3
	EIF2AK4	ENST00000917949.1		c.115C>G	p.Gln39Glu	missense	Exon 1 of 40	ENSP00000588008.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240632 AF XY: 0.00

Gnomad AFR exome AF: 0.0000698

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.0000723 AC: 3 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000829 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.35	N
PhyloP100		1.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.14
Sift	Benign	0.23	T
Sift4G	Benign	0.064	T
Polyphen		0.016	B
Vest4		0.25
MVP		0.63
MPC		0.29
ClinPred		0.14	T
GERP RS		4.5
PromoterAI		-0.082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.23
gMVP		0.46
Mutation Taster		=76/24	polymorphism

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: rs771007706; hg19: chr15-40226511;