rs750529763

Variant names:

• chr2-88558953-T-A
• rs750529763
• NM_004836.7:c.3114A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-88558953-T-A
• chr2-88558953-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004836.7(EIF2AK3):​c.3114A>T​(p.Lys1038Asn) variant causes a missense 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1038R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.404
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16345754).

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.3114A>T	p.Lys1038Asn	missense	Exon 16 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.2661A>T	p.Lys887Asn	missense	Exon 16 of 17	NP_001300844.1	A0A804HIT4
	EIF2AK3-AS1	NR_110236.1		n.651-15561T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.3114A>T	p.Lys1038Asn	missense	Exon 16 of 17	ENSP00000307235.3	Q9NZJ5
	EIF2AK3	ENST00000415570.1	TSL:1	n.2783A>T		non_coding_transcript_exon	Exon 15 of 16
	EIF2AK3-AS1	ENST00000413234.1	TSL:1	n.651-15561T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.58	N
PhyloP100		-0.40
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.027
Sift	Benign	0.063	T
Sift4G	Benign	0.37	T
Polyphen		0.0030	B
Vest4		0.17
MutPred		0.42		Loss of methylation at K1038 (P = 0.0069)
MVP		0.81
MPC		0.40
ClinPred		0.68	D
GERP RS		2.7
Varity_R		0.15
gMVP		0.29
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs750529763; hg19: chr2-88858471;