rs201593811

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004836.7(EIF2AK3):c.154G>T(p.Ala52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000592 in 1,350,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A52T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

EIF2AK3
NM_004836.7 missense

Scores

Clinical Significance

Not reported in ClinVar

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

EIF2AK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21937218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7 link	c.154G>T	p.Ala52Ser	missense_variant	Exon 1 of 17	ENST00000303236.9	NP_004827.4	Q9NZJ5B3KY45
EIF2AK3	XM_047446430.1 link	c.154G>T	p.Ala52Ser	missense_variant	Exon 1 of 12		XP_047302386.1
EIF2AK3	XM_047446428.1 link	c.17+568G>T		intron_variant	Intron 1 of 16		XP_047302384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF2AK3	ENST00000303236.9 link	c.154G>T	p.Ala52Ser	missense_variant	Exon 1 of 17	1	NM_004836.7	ENSP00000307235.3	Q9NZJ5
EIF2AK3	ENST00000652099.1 link	n.151G>T		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000498211.1	A0A494BZR8
EIF2AK3	ENST00000682892.1 link	c.-145-13268G>T		intron_variant	Intron 2 of 17			ENSP00000507214.1	A0A804HIT4
EIF2AK3	ENST00000652423.1 link	n.126+28G>T		intron_variant	Intron 1 of 3			ENSP00000498948.1	A0A494C186

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

96344

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000592

AC:

AN:

1350788

Hom.:

Cov.:

AF XY:

0.00000600

AC XY:

AN XY:

666296

show subpopulations

African (AFR)

AF:

0.0000362

AC:

AN:

27652

American (AMR)

AF:

0.00

AC:

AN:

32170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23836

East Asian (EAS)

AF:

0.00

AC:

AN:

31406

South Asian (SAS)

AF:

0.00

AC:

AN:

76054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4108

European-Non Finnish (NFE)

AF:

0.00000657

AC:

AN:

1064788

Other (OTH)

AF:

0.00

AC:

AN:

56216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000395

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.11

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.81

PhyloP100

1.6

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.050

REVEL

Benign

0.083

Sift

Benign

0.34

Sift4G

Benign

0.51

Polyphen

0.011

Vest4

0.20

MutPred

0.16

Gain of glycosylation at A52 (P = 0.0015);

MVP

0.85

MPC

1.4

ClinPred

0.32

GERP RS

3.6

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.084

gMVP

0.30

Mutation Taster

=95/5

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over