rs867529

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001313915.2(EIF2AK3):c.-47C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.281 in 1,612,796 control chromosomes in the GnomAD database, including 67,908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5255 hom., cov: 32)

Exomes 𝑓: 0.29 ( 62653 hom. )

Consequence

EIF2AK3
NM_001313915.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.89

Publications

63 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 Gene-Disease associations (from GenCC):

Wolcott-Rallison syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

EIF2AK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.620122E-4).

BP6

Variant 2-88613755-G-C is Benign according to our data. Variant chr2-88613755-G-C is described in ClinVar as Benign. ClinVar VariationId is 128987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001313915.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK3	NM_004836.7	MANE Select	c.407C>G	p.Ser136Cys	missense	Exon 2 of 17	NP_004827.4
EIF2AK3	NM_001313915.2		c.-47C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	NP_001300844.1	A0A804HIT4
EIF2AK3	NM_001313915.2		c.-47C>G		5_prime_UTR	Exon 2 of 17	NP_001300844.1	A0A804HIT4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.407C>G	p.Ser136Cys	missense	Exon 2 of 17	ENSP00000307235.3	Q9NZJ5
EIF2AK3	ENST00000682892.1		c.-47C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	ENSP00000507214.1	A0A804HIT4
EIF2AK3	ENST00000682892.1		c.-47C>G		5_prime_UTR	Exon 3 of 18	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35361

AN:

151874

Hom.:

5251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0557

Gnomad AMI

AF:

0.329

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.219

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.385

Gnomad FIN

AF:

0.349

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.278

GnomAD2 exomes

AF:

0.303

AC:

76063

AN:

251374

AF XY:

0.308

show subpopulations

Gnomad AFR exome

AF:

0.0487

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.225

Gnomad EAS exome

AF:

0.496

Gnomad FIN exome

AF:

0.348

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.306

GnomAD4 exome

AF:

0.286

AC:

417171

AN:

1460804

Hom.:

62653

Cov.:

AF XY:

0.288

AC XY:

209247

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.0468

AC:

1568

AN:

33474

American (AMR)

AF:

0.323

AC:

14433

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

6048

AN:

26122

East Asian (EAS)

AF:

0.453

AC:

17966

AN:

39688

South Asian (SAS)

AF:

0.380

AC:

32757

AN:

86236

European-Finnish (FIN)

AF:

0.343

AC:

18309

AN:

53406

Middle Eastern (MID)

AF:

0.256

AC:

1477

AN:

5768

European-Non Finnish (NFE)

AF:

0.277

AC:

307842

AN:

1111016

Other (OTH)

AF:

0.278

AC:

16771

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

15168

30336

45505

60673

75841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10460

20920

31380

41840

52300

<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:

0.233

AC:

35372

AN:

151992

Hom.:

5255

Cov.:

AF XY:

0.242

AC XY:

18003

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.0555

AC:

2303

AN:

41490

American (AMR)

AF:

0.320

AC:

4889

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

760

AN:

3468

East Asian (EAS)

AF:

0.474

AC:

2445

AN:

5158

South Asian (SAS)

AF:

0.387

AC:

1857

AN:

4794

European-Finnish (FIN)

AF:

0.349

AC:

3681

AN:

10548

Middle Eastern (MID)

AF:

0.260

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.272

AC:

18471

AN:

67940

Other (OTH)

AF:

0.280

AC:

590

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1282

2563

3845

5126

6408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.265

Hom.:

4347

Bravo

AF:

0.220

TwinsUK

AF:

0.284

AC:

1053

ALSPAC

AF:

0.281

AC:

1083

ESP6500AA

AF:

0.0581

AC:

256

ESP6500EA

AF:

0.270

AC:

2324

ExAC

AF:

0.298

AC:

36209

Asia WGS

AF:

0.370

AC:

1284

AN:

3478

EpiCase

AF:

0.263

EpiControl

AF:

0.269

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Wolcott-Rallison dysplasia (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.23

Eigen

Benign

0.0099

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.80

MetaRNN

Benign

0.00056

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.3

PhyloP100

5.9

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

REVEL

Benign

0.061

Sift

Benign

0.13

Sift4G

Benign

0.22

Polyphen

0.0020

Vest4

0.079

MPC

0.34

ClinPred

0.015

GERP RS

5.4

Varity_R

0.24

gMVP

0.56

Mutation Taster

=88/12

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over