chr2-88557328-A-C

Variant names:

• chr2-88557328-A-C
• rs148457589
• NM_004836.7:c.*408T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004836.7(EIF2AK3):​c.*408T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 176,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.240
• 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 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)

EIF2AK3-AS1 (HGNC:58177):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000532 (81/152338) while in subpopulation AFR AF = 0.00192 (80/41578). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*408T>G		3_prime_UTR	Exon 17 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.*408T>G		3_prime_UTR	Exon 17 of 17	NP_001300844.1	A0A804HIT4
	EIF2AK3-AS1	NR_110236.1		n.650+17149A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.*408T>G		3_prime_UTR	Exon 17 of 17	ENSP00000307235.3	Q9NZJ5
	EIF2AK3-AS1	ENST00000413234.1	TSL:1	n.650+17149A>C		intron	N/A
	EIF2AK3	ENST00000682892.1		c.*408T>G		3_prime_UTR	Exon 18 of 18	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 1 AN: 23742 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 12336

African (AFR) AF: 0.00 AC: 0 AN: 430

American (AMR) AF: 0.000349 AC: 1 AN: 2866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 462

East Asian (EAS) AF: 0.00 AC: 0 AN: 1708

South Asian (SAS) AF: 0.00 AC: 0 AN: 2602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 64

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 13204

Other (OTH) AF: 0.00 AC: 0 AN: 1170

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74492

African (AFR) AF: 0.00192 AC: 80 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000691

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Wolcott-Rallison dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.057
DANN	Benign	0.75
PhyloP100		-0.24

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

Other links and lift over

dbSNP: rs148457589; hg19: chr2-88856846;