NM_004836.7:c.407C>A

Variant names:

• chr2-88613755-G-T
• rs867529
• NM_004836.7:c.407C>A

Variant summary

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

The NM_004836.7(EIF2AK3):​c.407C>A​(p.Ser136Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S136C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2AK3 NM_004836.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89
• Publications: 63 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.407C>A	p.Ser136Tyr	missense	Exon 2 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.-47C>A		5_prime_UTR	Exon 2 of 17	NP_001300844.1	A0A804HIT4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2AK3	ENST00000303236.9	TSL:1 MANE Select	c.407C>A	p.Ser136Tyr	missense	Exon 2 of 17	ENSP00000307235.3	Q9NZJ5
	EIF2AK3	ENST00000682892.1		c.-47C>A		5_prime_UTR	Exon 3 of 18	ENSP00000507214.1	A0A804HIT4
	EIF2AK3	ENST00000652099.1		n.404C>A		non_coding_transcript_exon	Exon 2 of 18	ENSP00000498211.1	A0A494BZR8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.14
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.011	D
Polyphen		0.92	P
Vest4		0.45
MutPred		0.30		Loss of disorder (P = 0.0024)
MVP		0.91
MPC		0.92
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.37
gMVP		0.63
Mutation Taster		=82/18	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

dbSNP: rs867529; hg19: chr2-88913273;