15-39934294-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001013703.4(EIF2AK4):c.99T>C(p.Ile33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,611,938 control chromosomes in the GnomAD database, including 627,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63084 hom., cov: 33)
  • Exomes 𝑓: 0.88 (564024 hom.)
• Consequence: EIF2AK4 NM_001013703.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.310

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 15-39934294-T-C is Benign according to our data. Variant chr15-39934294-T-C is described in ClinVar as [Benign]. Clinvar id is 381178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-39934294-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.99T>C	p.Ile33=	synonymous_variant	1/39	ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.99T>C	p.Ile33=	synonymous_variant	1/39	2	NM_001013703.4	P1
EIF2AK4	ENST00000559624.5	c.99T>C	p.Ile33=	synonymous_variant	1/11	1
EIF2AK4	ENST00000560648.1	c.99T>C	p.Ile33=	synonymous_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138230 AN: 152118 Hom.: 63018 Cov.: 33

Gnomad AFR AF: 0.975

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.983

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.901

GnomAD3 exomes AF: 0.910 AC: 220106 AN: 241960 Hom.: 100464 AF XY: 0.909 AC XY: 120263 AN XY: 132234

Gnomad AFR exome AF: 0.977

Gnomad AMR exome AF: 0.925

Gnomad ASJ exome AF: 0.919

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.982

Gnomad FIN exome AF: 0.926

Gnomad NFE exome AF: 0.857

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.878 AC: 1281702 AN: 1459702 Hom.: 564024 Cov.: 67 AF XY: 0.881 AC XY: 639509 AN XY: 726098

Gnomad4 AFR exome AF: 0.979

Gnomad4 AMR exome AF: 0.922

Gnomad4 ASJ exome AF: 0.914

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.981

Gnomad4 FIN exome AF: 0.921

Gnomad4 NFE exome AF: 0.857

Gnomad4 OTH exome AF: 0.893

GnomAD4 genome AF: 0.909 AC: 138355 AN: 152236 Hom.: 63084 Cov.: 33 AF XY: 0.913 AC XY: 67968 AN XY: 74436

Gnomad4 AFR AF: 0.975

Gnomad4 AMR AF: 0.896

Gnomad4 ASJ AF: 0.912

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.983

Gnomad4 FIN AF: 0.928

Gnomad4 NFE AF: 0.857

Gnomad4 OTH AF: 0.902

Alfa AF: 0.870 Hom.: 72546

Bravo AF: 0.909

Asia WGS AF: 0.988 AC: 3437 AN: 3478

EpiCase AF: 0.864

EpiControl AF: 0.866

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Familial pulmonary capillary hemangiomatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs566792; hg19: chr15-40226495; COSMIC: COSV55465589;