rs201593811

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.154G>A(p.Ala52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,502,868 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A52A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0048 ( 20 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.56

Publications

12 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

EIF2AK3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_004836.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0064079165).

BP6

Variant 2-88627121-C-T is Benign according to our data. Variant chr2-88627121-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00359 (546/152088) while in subpopulation NFE AF = 0.00577 (392/67958). AF 95% confidence interval is 0.0053. There are 1 homozygotes in GnomAd4. There are 267 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 20 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.154G>A	p.Ala52Thr	missense	Exon 1 of 17	NP_004827.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.154G>A	p.Ala52Thr	missense	Exon 1 of 17	ENSP00000307235.3	Q9NZJ5
EIF2AK3	ENST00000682892.1		c.-145-13268G>A		intron	N/A	ENSP00000507214.1	A0A804HIT4
EIF2AK3	ENST00000652099.1		n.151G>A		non_coding_transcript_exon	Exon 1 of 18	ENSP00000498211.1	A0A494BZR8

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

544

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00599

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00577

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00460

AC:

443

AN:

96344

AF XY:

0.00483

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.000147

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00863

Gnomad NFE exome

AF:

0.00703

Gnomad OTH exome

AF:

0.00830

GnomAD4 exome

AF:

0.00480

AC:

6483

AN:

1350780

Hom.:

Cov.:

AF XY:

0.00472

AC XY:

3147

AN XY:

666292

show subpopulations

African (AFR)

AF:

0.000868

AC:

AN:

27652

American (AMR)

AF:

0.00277

AC:

AN:

32170

Ashkenazi Jewish (ASJ)

AF:

0.000168

AC:

AN:

23836

East Asian (EAS)

AF:

0.00

AC:

AN:

31406

South Asian (SAS)

AF:

0.00312

AC:

237

AN:

76054

European-Finnish (FIN)

AF:

0.00984

AC:

340

AN:

34558

Middle Eastern (MID)

AF:

0.00292

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.00521

AC:

5546

AN:

1064782

Other (OTH)

AF:

0.00411

AC:

231

AN:

56216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

410

820

1231

1641

2051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.00359

AC:

546

AN:

152088

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41552

American (AMR)

AF:

0.00138

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00331

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00599

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00577

AC:

392

AN:

67958

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

103

129

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:

0.00511

Hom.:

Bravo

AF:

0.00287

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Wolcott-Rallison dysplasia (3)

Connective tissue disorder (1)

EIF2AK3-related disorder (1)

Monogenic diabetes (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PhyloP100

1.6

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.25

REVEL

Benign

0.069

Sift

Benign

0.19

Sift4G

Benign

0.31

PromoterAI

-0.0046

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.078

gMVP

0.40

Mutation Taster

=98/2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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