rs17720604

Variant names:

• chr15-39953725-G-A
• rs17720604
• NM_001013703.4:c.514-179G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001013703.4(EIF2AK4):​c.514-179G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,238 control chromosomes in the GnomAD database, including 938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (938 hom., cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.85
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 15-39953725-G-A is Benign according to our data. Variant chr15-39953725-G-A is described in ClinVar as Benign. ClinVar VariationId is 674892.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.21 is higher than 0.05.

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.514-179G>A		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.514-179G>A		intron	N/A	ENSP00000263791.5	Q9P2K8-1
	EIF2AK4	ENST00000559624.5	TSL:1	c.514-179G>A		intron	N/A	ENSP00000453148.1	Q9P2K8-3
	EIF2AK4	ENST00000917949.1		c.514-179G>A		intron	N/A	ENSP00000588008.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16134 AN: 152120 Hom.: 938 Cov.: 33

Gnomad AFR AF: 0.0925

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0909

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0570

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.0872

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.110

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

GnomAD4 genome AF: 0.106 AC: 16134 AN: 152238 Hom.: 938 Cov.: 33 AF XY: 0.109 AC XY: 8095 AN XY: 74436

African (AFR) AF: 0.0923 AC: 3835 AN: 41546

American (AMR) AF: 0.0908 AC: 1388 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 486 AN: 3470

East Asian (EAS) AF: 0.0567 AC: 294 AN: 5184

South Asian (SAS) AF: 0.221 AC: 1066 AN: 4828

European-Finnish (FIN) AF: 0.0872 AC: 924 AN: 10598

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7765 AN: 68004

Other (OTH) AF: 0.108 AC: 228 AN: 2110

Alfa AF: 0.112 Hom.: 1204

Bravo AF: 0.101

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.021
DANN	Benign	0.63
PhyloP100		-2.9
PromoterAI		-0.12	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: rs17720604; hg19: chr15-40245926;