Genetic Variant EIF2AK3-DT:n.1195-1182T>G (chr2-88630218-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000682892.1(EIF2AK3):c.-145-16365A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,060 control chromosomes in the GnomAD database, including 7,520 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.29 ( 7520 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

EIF2AK3
ENST00000682892.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.349

Publications

6 publications found

Variant links:

Genes affected

EIF2AK3-DT (HGNC:54066): (EIF2AK3 divergent transcript)

EIF2AK3-DT links:

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

EIF2AK3 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript ENST00000682892.1, 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000682892.1. 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-DT	NR_135540.1		n.905-1182T>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EIF2AK3-DT	ENST00000453008.4	TSL:1	n.1195-1182T>G	intron	N/A
EIF2AK3	ENST00000682892.1		c.-145-16365A>C	intron	N/A	ENSP00000507214.1	A0A804HIT4
EIF2AK3-DT	ENST00000606164.1	TSL:6	n.2048T>G	non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.289

AC:

43866

AN:

151940

Hom.:

7509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.380

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.511

Gnomad SAS

AF:

0.471

Gnomad FIN

AF:

0.408

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.321

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.289

AC:

43890

AN:

152060

Hom.:

7520

Cov.:

AF XY:

0.298

AC XY:

22123

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.105

AC:

4347

AN:

41480

American (AMR)

AF:

0.380

AC:

5814

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

933

AN:

3468

East Asian (EAS)

AF:

0.511

AC:

2637

AN:

5162

South Asian (SAS)

AF:

0.473

AC:

2281

AN:

4820

European-Finnish (FIN)

AF:

0.408

AC:

4309

AN:

10570

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.331

AC:

22483

AN:

67966

Other (OTH)

AF:

0.324

AC:

682

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1503

3006

4509

6012

7515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.247

Hom.:

1341

Bravo

AF:

0.275

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.35

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over