rs797045558
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004836.7(EIF2AK3):c.1564_1565delTG(p.Trp522GlufsTer34) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
EIF2AK3
NM_004836.7 frameshift
NM_004836.7 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.98
Publications
0 publications found
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 syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-88585925-CCA-C is Pathogenic according to our data. Variant chr2-88585925-CCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 210932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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.1564_1565delTG | p.Trp522GlufsTer34 | frameshift | Exon 9 of 17 | NP_004827.4 | ||
| EIF2AK3 | NM_001313915.2 | c.1111_1112delTG | p.Trp371GlufsTer34 | frameshift | Exon 9 of 17 | NP_001300844.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EIF2AK3 | ENST00000303236.9 | TSL:1 MANE Select | c.1564_1565delTG | p.Trp522GlufsTer34 | frameshift | Exon 9 of 17 | ENSP00000307235.3 | ||
| EIF2AK3 | ENST00000415570.1 | TSL:1 | n.1233_1234delTG | non_coding_transcript_exon | Exon 8 of 16 | ||||
| EIF2AK3 | ENST00000682892.1 | c.1111_1112delTG | p.Trp371GlufsTer34 | frameshift | Exon 10 of 18 | ENSP00000507214.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461834Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727218 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461834
Hom.:
AF XY:
AC XY:
1
AN XY:
727218
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26132
East Asian (EAS)
AF:
AC:
0
AN:
39690
South Asian (SAS)
AF:
AC:
1
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111972
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
1
-
-
Wolcott-Rallison dysplasia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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