NM_004836.7:c.3339G>A

Variant names:

• chr2-88557748-C-T
• NM_004836.7:c.3339G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004836.7(EIF2AK3):​c.3339G>A​(p.Leu1113Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L1113L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK3 NM_004836.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.93
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 2-88557748-C-T is Benign according to our data. Variant chr2-88557748-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2825535.Status of the report is criteria_provided_single_submitter, 1 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.3339G>A	p.Leu1113Leu	synonymous	Exon 17 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.2886G>A	p.Leu962Leu	synonymous	Exon 17 of 17	NP_001300844.1	A0A804HIT4
	EIF2AK3-AS1	NR_110236.1		n.651-16766C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.3339G>A	p.Leu1113Leu	synonymous	Exon 17 of 17	ENSP00000307235.3	Q9NZJ5
	EIF2AK3-AS1	ENST00000413234.1	TSL:1	n.651-16766C>T		intron	N/A
	EIF2AK3	ENST00000682892.1		c.2886G>A	p.Leu962Leu	synonymous	Exon 18 of 18	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

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

hg19: chr2-88857266;