rs1805165

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_004836.7(EIF2AK3):c.2110G>T(p.Ala704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 1,613,760 control chromosomes in the GnomAD database, including 421,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A704V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.77 ( 45971 hom., cov: 32)

Exomes 𝑓: 0.71 ( 375836 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.73

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

EIF2AK3 links:

ENSG00000225420 (HGNC:58177):

ENSG00000225420 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=5.5892735E-7).

BP6

Variant 2-88575373-C-A is Benign according to our data. Variant chr2-88575373-C-A is described in ClinVar as Benign. ClinVar VariationId is 128986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2AK3	NM_004836.7	MANE Select	c.2110G>T	p.Ala704Ser	missense	Exon 13 of 17	NP_004827.4
EIF2AK3	NM_001313915.2		c.1657G>T	p.Ala553Ser	missense	Exon 13 of 17	NP_001300844.1
EIF2AK3-AS1	NR_110236.1		n.1510C>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.2110G>T	p.Ala704Ser	missense	Exon 13 of 17	ENSP00000307235.3
ENSG00000225420	ENST00000413234.1	TSL:1	n.1510C>A		non_coding_transcript_exon	Exon 3 of 3
EIF2AK3	ENST00000415570.1	TSL:1	n.1779G>T		non_coding_transcript_exon	Exon 12 of 16

Frequencies

GnomAD3 genomes

AF:

0.768

AC:

116690

AN:

151990

Hom.:

45919

Cov.:

show subpopulations

Gnomad AFR

AF:

0.944

Gnomad AMI

AF:

0.674

Gnomad AMR

AF:

0.682

Gnomad ASJ

AF:

0.784

Gnomad EAS

AF:

0.525

Gnomad SAS

AF:

0.618

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.752

Gnomad NFE

AF:

0.728

Gnomad OTH

AF:

0.724

GnomAD2 exomes

AF:

0.698

AC:

175097

AN:

251010

AF XY:

0.692

show subpopulations

Gnomad AFR exome

AF:

0.951

Gnomad AMR exome

AF:

0.679

Gnomad ASJ exome

AF:

0.777

Gnomad EAS exome

AF:

0.504

Gnomad FIN exome

AF:

0.653

Gnomad NFE exome

AF:

0.721

Gnomad OTH exome

AF:

0.694

GnomAD4 exome

AF:

0.714

AC:

1044020

AN:

1461652

Hom.:

375836

Cov.:

AF XY:

0.712

AC XY:

517684

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.953

AC:

31906

AN:

33478

American (AMR)

AF:

0.678

AC:

30313

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.770

AC:

20134

AN:

26136

East Asian (EAS)

AF:

0.548

AC:

21763

AN:

39694

South Asian (SAS)

AF:

0.620

AC:

53490

AN:

86258

European-Finnish (FIN)

AF:

0.657

AC:

35008

AN:

53248

Middle Eastern (MID)

AF:

0.744

AC:

4292

AN:

5766

European-Non Finnish (NFE)

AF:

0.723

AC:

803473

AN:

1111956

Other (OTH)

AF:

0.723

AC:

43641

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

18538

37077

55615

74154

92692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19880

39760

59640

79520

99400

<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:

0.768

AC:

116797

AN:

152108

Hom.:

45971

Cov.:

AF XY:

0.759

AC XY:

56399

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.945

AC:

39238

AN:

41540

American (AMR)

AF:

0.682

AC:

10401

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.784

AC:

2721

AN:

3472

East Asian (EAS)

AF:

0.526

AC:

2713

AN:

5156

South Asian (SAS)

AF:

0.616

AC:

2971

AN:

4826

European-Finnish (FIN)

AF:

0.653

AC:

6890

AN:

10548

Middle Eastern (MID)

AF:

0.747

AC:

218

AN:

292

European-Non Finnish (NFE)

AF:

0.728

AC:

49510

AN:

68000

Other (OTH)

AF:

0.722

AC:

1523

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1302

2604

3907

5209

6511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.736

Hom.:

161734

Bravo

AF:

0.780

TwinsUK

AF:

0.716

AC:

2654

ALSPAC

AF:

0.719

AC:

2771

ESP6500AA

AF:

0.942

AC:

4150

ESP6500EA

AF:

0.730

AC:

6277

ExAC

AF:

0.702

AC:

85213

Asia WGS

AF:

0.630

AC:

2194

AN:

3478

EpiCase

AF:

0.736

EpiControl

AF:

0.731

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Wolcott-Rallison dysplasia (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.080

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.067

MetaRNN

Benign

5.6e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.090

PhyloP100

2.7

PrimateAI

Benign

0.42

PROVEAN

Benign

1.1

REVEL

Benign

0.099

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.034

MPC

0.31

ClinPred

0.0043

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.20

Mutation Taster

=98/2

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over