rs144057685

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.256

Variant links:

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]

EIF2AK3 links:

EIF2AK3-DT (HGNC:54066): (EIF2AK3 divergent transcript)

EIF2AK3-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	XM_047446428.1 link	c.17+214A>G	intron_variant	Intron 1 of 16		XP_047302384.1
EIF2AK3	NM_004836.7 link	c.-201A>G	upstream_gene_variant		ENST00000303236.9	NP_004827.4	Q9NZJ5B3KY45
EIF2AK3	XM_047446430.1 link	c.-201A>G	upstream_gene_variant			XP_047302386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9 link	c.-201A>G		upstream_gene_variant		1	NM_004836.7	ENSP00000307235.3		Q9NZJ5

Frequencies

GnomAD3 genomes

AF:

0.00661

AC:

1006

AN:

152200

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00863

AC XY:

1879

AN XY:

217852

show subpopulations

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.:

Cov.:

AF XY:

0.00596

AC XY:

444

AN XY:

74488

show subpopulations

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.:

Bravo

AF:

0.00625

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EIF2AK3: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Uncertain:1

Jun 15, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wolcott-Rallison dysplasia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.30

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over