rs35226268

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_StrongBS1BS2

The NM_004836.7(EIF2AK3):c.2014G>A(p.Glu672Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,120 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00098 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 23 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.37

Publications

9 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=0.0054520965).

BP6

Variant 2-88576576-C-T is Benign according to our data. Variant chr2-88576576-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000978 (149/152282) while in subpopulation EAS AF = 0.0219 (113/5170). AF 95% confidence interval is 0.0186. There are 2 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004836.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	NM_004836.7	MANE Select	c.2014G>A	p.Glu672Lys	missense	Exon 12 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.1561G>A	p.Glu521Lys	missense	Exon 12 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.2014G>A	p.Glu672Lys	missense	Exon 12 of 17	ENSP00000307235.3	Q9NZJ5
EIF2AK3	ENST00000415570.1	TSL:1	n.1683G>A		non_coding_transcript_exon	Exon 11 of 16
EIF2AK3	ENST00000682892.1		c.1561G>A	p.Glu521Lys	missense	Exon 13 of 18	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes

AF:

0.000986

AC:

150

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0220

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00203

AC:

509

AN:

251252

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0234

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.00104

AC:

1522

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

741

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0313

AC:

1244

AN:

39690

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00221

AC:

118

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000827

AC:

AN:

1111976

Other (OTH)

AF:

0.000861

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000978

AC:

149

AN:

152282

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.000261

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0219

AC:

113

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68024

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000647

Hom.:

Bravo

AF:

0.000986

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00215

AC:

261

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Wolcott-Rallison dysplasia (2)

EIF2AK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.012

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.17

PhyloP100

2.4

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.12

REVEL

Benign

0.12

Sift

Benign

0.59

Sift4G

Benign

0.96

Polyphen

0.022

Vest4

0.30

MVP

0.69

MPC

0.39

ClinPred

0.032

GERP RS

5.4

Varity_R

0.12

gMVP

0.35

Mutation Taster

=78/22

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

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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