rs1085307445

Positions:

• chr15-40032237-TGTAAGTGGCTTTC-TTTCT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001013703.4(EIF2AK4):​c.4728+1_4728+13delGTAAGTGGCTTTCinsTTCT variant causes a splice donor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.42

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013737374 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40032238-GTAAGTGGCTTTC-TTCT is Pathogenic according to our data. Variant chr15-40032238-GTAAGTGGCTTTC-TTCT is described in ClinVar as [Pathogenic]. Clinvar id is 426064.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.4728+1_4728+13delGTAAGTGGCTTTCinsTTCT		splice_donor_variant, splice_region_variant, intron_variant		ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.4728+1_4728+13delGTAAGTGGCTTTCinsTTCT		splice_donor_variant, splice_region_variant, intron_variant		2	NM_001013703.4	ENSP00000263791.5

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial pulmonary capillary hemangiomatosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Rare Disease Genomics Group, St George's University of London

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1085307445; hg19: chr15-40324439;