15-39943033-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001013703.4(EIF2AK4):c.258-350T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0925 in 152,084 control chromosomes in the GnomAD database, including 815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.093 (815 hom., cov: 32)
• Consequence: EIF2AK4 NM_001013703.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.146

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-39943033-T-C is Benign according to our data. Variant chr15-39943033-T-C is described in ClinVar as [Benign]. Clinvar id is 1243175.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK4	NM_001013703.4	c.258-350T>C		intron_variant		ENST00000263791.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.258-350T>C		intron_variant		2	NM_001013703.4	P1
EIF2AK4	ENST00000559624.5	c.258-350T>C		intron_variant		1
EIF2AK4	ENST00000560648.1	c.258-350T>C		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0926 AC: 14065 AN: 151968 Hom.: 816 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0901

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0572

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.0868

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.0925 AC: 14070 AN: 152084 Hom.: 815 Cov.: 32 AF XY: 0.0952 AC XY: 7081 AN XY: 74364

Gnomad4 AFR AF: 0.0319

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0572

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.0868

Gnomad4 NFE AF: 0.120

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0982 Hom.: 89

Bravo AF: 0.0847

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.3
Dann	Benign	0.68

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: rs34513040; hg19: chr15-40235234;