15-39976797-G-GGACGAC

Variant names:

• chr15-39976797-G-GGACGAC
• rs377237751
• NM_001013703.4:c.2208_2213dupCGACGA

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001013703.4(EIF2AK4):​c.2208_2213dupCGACGA​(p.Asp736_Asp737dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,574,298 control chromosomes in the GnomAD database, including 10,196 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (734 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9462 hom.)
• Consequence: EIF2AK4 NM_001013703.4 disruptive_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.78

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 -15 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 15-39976797-G-GGACGAC is Benign according to our data. Variant chr15-39976797-G-GGACGAC is described in ClinVar as [Benign]. Clinvar id is 402821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK4	NM_001013703.4	c.2208_2213dupCGACGA	p.Asp736_Asp737dup	disruptive_inframe_insertion	Exon 12 of 39	ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.2208_2213dupCGACGA	p.Asp736_Asp737dup	disruptive_inframe_insertion	Exon 12 of 39	2	NM_001013703.4	ENSP00000263791.5
EIF2AK4	ENST00000560855.5	c.1623_1628dupCGACGA	p.Asp541_Asp542dup	disruptive_inframe_insertion	Exon 8 of 34	5		ENSP00000453575.1

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 12947 AN: 152202 Hom.: 734 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.0848

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0965

GnomAD3 exomes AF: 0.0989 AC: 20279 AN: 205028 Hom.: 1347 AF XY: 0.107 AC XY: 12096 AN XY: 113398

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.0552

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.0687

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.109 AC: 155655 AN: 1421982 Hom.: 9462 Cov.: 31 AF XY: 0.113 AC XY: 79605 AN XY: 705002

Gnomad4 AFR exome AF: 0.0217

Gnomad4 AMR exome AF: 0.0598

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.0651

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.0769

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0850 AC: 12945 AN: 152316 Hom.: 734 Cov.: 32 AF XY: 0.0885 AC XY: 6591 AN XY: 74470

Gnomad4 AFR AF: 0.0253

Gnomad4 AMR AF: 0.0847

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.0635

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.0840

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.0950

Alfa AF: 0.0622 Hom.: 91

Asia WGS AF: 0.114 AC: 397 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Dec 11, 2017

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

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. -

not provided Benign:2

Dec 12, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial pulmonary capillary hemangiomatosis Benign:1

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs377237751; hg19: chr15-40268998;