rs144057685

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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

Publications

3 publications found

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 was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 2-88627475-T-C is Benign according to our data. Variant chr2-88627475-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337426.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

African (AFR)

AF:

0.000916

AC:

AN:

9824

American (AMR)

AF:

0.00372

AC:

AN:

7258

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

321

AN:

10182

East Asian (EAS)

AF:

0.00

AC:

AN:

22604

South Asian (SAS)

AF:

0.000648

AC:

AN:

16988

European-Finnish (FIN)

AF:

0.00684

AC:

152

AN:

22234

Middle Eastern (MID)

AF:

0.00982

AC:

AN:

1630

European-Non Finnish (NFE)

AF:

0.00922

AC:

2959

AN:

320796

Other (OTH)

AF:

0.00794

AC:

177

AN:

22286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

191

382

572

763

954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00660

AC:

1005

AN:

152318

Hom.:

Cov.:

AF XY:

0.00596

AC XY:

444

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41580

American (AMR)

AF:

0.00385

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00583

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

714

AN:

68010

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.83

PhyloP100

0.26

PromoterAI

-0.084

Neutral

(source)

Mutation Taster

=298/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over