rs776140816

Variant names:

• chr15-40017243-G-C
• rs776140816
• NM_001013703.4:c.4065+1G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-40017243-G-C
• chr15-40017243-G-T
• chr15-40017243-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001013703.4(EIF2AK4):​c.4065+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EIF2AK4 NM_001013703.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.96
• 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

ENSG00000306490 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.027272727 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 15-40017243-G-C is Pathogenic according to our data. Variant chr15-40017243-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 426062.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK4	NM_001013703.4	MANE Select	c.4065+1G>C		splice_donor intron	N/A	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.4065+1G>C		splice_donor intron	N/A	ENSP00000263791.5	Q9P2K8-1
	EIF2AK4	ENST00000558629.5	TSL:1	n.2982+1G>C		splice_donor intron	N/A
	EIF2AK4	ENST00000917949.1		c.4107+1G>C		splice_donor intron	N/A	ENSP00000588008.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457706 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724572

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108552

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		10
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs776140816; hg19: chr15-40309444;