rs121908569

Positions:

• chr2-88583430-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004836.7(EIF2AK3):​c.1763G>A​(p.Arg588Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,451,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-88583430-C-T is Pathogenic according to our data. Variant chr2-88583430-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5875.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.1763G>A	p.Arg588Gln	missense_variant, splice_region_variant	10/17	ENST00000303236.9	NP_004827.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.1763G>A	p.Arg588Gln	missense_variant, splice_region_variant	10/17	1	NM_004836.7	ENSP00000307235	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451472 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 722762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Wolcott-Rallison dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	.;D;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.78		.;Loss of phosphorylation at T591 (P = 0.1065);.;
MVP		0.87
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908569; hg19: chr2-88882948; COSMIC: COSV57548278; COSMIC: COSV57548278;