rs1085307439

Variant names:

• chr15-39943476-CTG-C
• rs1085307439
• NM_001013703.4:c.354_355delTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001013703.4(EIF2AK4):​c.354_355delTG​(p.Cys118TrpfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,425,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EIF2AK4 NM_001013703.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.62
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-39943476-CTG-C is Pathogenic according to our data. Variant chr15-39943476-CTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 426050.Status of the report is no_assertion_criteria_provided, 0 stars.

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.354_355delTG	p.Cys118TrpfsTer7	frameshift	Exon 3 of 39	NP_001013725.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	ENST00000263791.10	TSL:2 MANE Select	c.354_355delTG	p.Cys118TrpfsTer7	frameshift	Exon 3 of 39	ENSP00000263791.5
	EIF2AK4	ENST00000559624.5	TSL:1	c.354_355delTG	p.Cys118TrpfsTer7	frameshift	Exon 3 of 11	ENSP00000453148.1
	EIF2AK4	ENST00000560648.1	TSL:3	c.354_355delTG	p.Cys118TrpfsTer66	frameshift	Exon 3 of 4	ENSP00000453968.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1425806 Hom.: 0 AF XY: 0.00000141 AC XY: 1 AN XY: 707910

African (AFR) AF: 0.00 AC: 0 AN: 31070

American (AMR) AF: 0.00 AC: 0 AN: 37148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25432

East Asian (EAS) AF: 0.00 AC: 0 AN: 37756

South Asian (SAS) AF: 0.00 AC: 0 AN: 77180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099462

Other (OTH) AF: 0.00 AC: 0 AN: 59064

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Familial pulmonary capillary hemangiomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1085307439; hg19: chr15-40235677;