rs144057685

Positions:

• chr2-88627475-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The ENST00000682892.1(EIF2AK3):​c.-145-13622A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 586,120 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (26 hom.)
• Consequence: EIF2AK3 ENST00000682892.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.256

Genes affected

EIF2AK3 (HGNC:3255): (eukaryotic translation initiation factor 2 alpha kinase 3) The protein encoded by this gene phosphorylates the alpha subunit of eukaryotic translation-initiation factor 2, leading to its inactivation, and thus to a rapid reduction of translational initiation and repression of global protein synthesis. This protein is thought to modulate mitochondrial function. It is a type I membrane protein located in the endoplasmic reticulum (ER), where it is induced by ER stress caused by malfolded proteins. Mutations in this gene are associated with Wolcott-Rallison syndrome. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0066 (1005/152318) while in subpopulation NFE AF= 0.0105 (714/68010). AF 95% confidence interval is 0.00986. There are 4 homozygotes in gnomad4. There are 444 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK3	XM_047446428.1	c.17+214A>G		intron_variant			XP_047302384.1
EIF2AK3	NM_004836.7			upstream_gene_variant		ENST00000303236.9	NP_004827.4
EIF2AK3	XM_047446430.1			upstream_gene_variant			XP_047302386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000682892.1	c.-145-13622A>G		intron_variant				ENSP00000507214
EIF2AK3	ENST00000303236.9			upstream_gene_variant		1	NM_004836.7	ENSP00000307235	P1
EIF2AK3	ENST00000652423.1			upstream_gene_variant				ENSP00000498948

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152200 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.00846 AC: 3672 AN: 433802 Hom.: 26 Cov.: 6 AF XY: 0.00863 AC XY: 1879 AN XY: 217852

Gnomad4 AFR exome AF: 0.000916

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000648

Gnomad4 FIN exome AF: 0.00684

Gnomad4 NFE exome AF: 0.00922

Gnomad4 OTH exome AF: 0.00794

GnomAD4 genome AF: 0.00660 AC: 1005 AN: 152318 Hom.: 4 Cov.: 32 AF XY: 0.00596 AC XY: 444 AN XY: 74488

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00583

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00683 Hom.: 0

Bravo AF: 0.00625

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	EIF2AK3: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 15, 2017

- -

Wolcott-Rallison dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.83

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: rs144057685; hg19: chr2-88926993;