15-39939800-C-A

Position:

• chr15-39939800-C-A

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.257+183C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 152,038 control chromosomes in the GnomAD database, including 10,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.34 (10119 hom., cov: 33)
• Consequence: EIF2AK4 NM_001013703.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.399

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=-0.8).
• BP6: Variant 15-39939800-C-A is Benign according to our data. Variant chr15-39939800-C-A is described in ClinVar as [Benign]. Clinvar id is 674661.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.257+183C>A		intron_variant		ENST00000263791.10	NP_001013725.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK4	ENST00000263791.10	c.257+183C>A		intron_variant		2	NM_001013703.4	ENSP00000263791	P1
EIF2AK4	ENST00000559624.5	c.257+183C>A		intron_variant		1		ENSP00000453148
EIF2AK4	ENST00000560648.1	c.257+183C>A		intron_variant		3		ENSP00000453968

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52219 AN: 151920 Hom.: 10104 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.355

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

GnomAD4 genome AF: 0.344 AC: 52280 AN: 152038 Hom.: 10119 Cov.: 33 AF XY: 0.354 AC XY: 26321 AN XY: 74302

Gnomad4 AFR AF: 0.373

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.563

Gnomad4 FIN AF: 0.300

Gnomad4 NFE AF: 0.259

Gnomad4 OTH AF: 0.357

Alfa AF: 0.219 Hom.: 714

Bravo AF: 0.357

Asia WGS AF: 0.650 AC: 2261 AN: 3478

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	-0.80
CADD	Benign	2.3
DANN	Benign	0.38

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: rs500200; hg19: chr15-40232001;