chr15-39939424-A-T

Position:

• chr15-39939424-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001013703.4(EIF2AK4):​c.145-81A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 723,644 control chromosomes in the GnomAD database, including 46,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10146 hom., cov: 33)
  • Exomes 𝑓: 0.33 (36465 hom.)
• Consequence: EIF2AK4 NM_001013703.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.387

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-39939424-A-T is Benign according to our data. Variant chr15-39939424-A-T is described in ClinVar as [Benign]. Clinvar id is 674660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.145-81A>T		intron_variant		ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.145-81A>T		intron_variant		2	NM_001013703.4	ENSP00000263791	P1
EIF2AK4	ENST00000559624.5	c.145-81A>T		intron_variant		1		ENSP00000453148
EIF2AK4	ENST00000560648.1	c.145-81A>T		intron_variant		3		ENSP00000453968

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52260 AN: 151980 Hom.: 10130 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.326 AC: 186257 AN: 571546 Hom.: 36465 AF XY: 0.328 AC XY: 95976 AN XY: 292496

Gnomad4 AFR exome AF: 0.377

Gnomad4 AMR exome AF: 0.556

Gnomad4 ASJ exome AF: 0.314

Gnomad4 EAS exome AF: 0.794

Gnomad4 SAS exome AF: 0.552

Gnomad4 FIN exome AF: 0.295

Gnomad4 NFE exome AF: 0.266

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.344 AC: 52322 AN: 152098 Hom.: 10146 Cov.: 33 AF XY: 0.354 AC XY: 26342 AN XY: 74342

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.356

Alfa AF: 0.143 Hom.: 247

Bravo AF: 0.357

Asia WGS AF: 0.650 AC: 2255 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs524240; hg19: chr15-40231625;