NM_004836.7:c.*175A>T

Variant names:

• chr2-88557561-T-A
• rs886056415
• NM_004836.7:c.*175A>T

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.*175A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000757 in 528,504 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: EIF2AK3 NM_004836.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.157
• 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=-0.61).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000757 (4/528504) while in subpopulation MID AF = 0.000869 (2/2302). AF 95% confidence interval is 0.000154. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 6. 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.*175A>T		3_prime_UTR	Exon 17 of 17	NP_004827.4
	EIF2AK3	NM_001313915.2		c.*175A>T		3_prime_UTR	Exon 17 of 17	NP_001300844.1	A0A804HIT4
	EIF2AK3-AS1	NR_110236.1		n.651-16953T>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.*175A>T		3_prime_UTR	Exon 17 of 17	ENSP00000307235.3	Q9NZJ5
	EIF2AK3-AS1	ENST00000413234.1	TSL:1	n.651-16953T>A		intron	N/A
	EIF2AK3	ENST00000682892.1		c.*175A>T		3_prime_UTR	Exon 18 of 18	ENSP00000507214.1	A0A804HIT4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000757 AC: 4 AN: 528504 Hom.: 0 Cov.: 6 AF XY: 0.00000710 AC XY: 2 AN XY: 281520

African (AFR) AF: 0.00 AC: 0 AN: 14496

American (AMR) AF: 0.00 AC: 0 AN: 27594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16694

East Asian (EAS) AF: 0.00 AC: 0 AN: 31986

South Asian (SAS) AF: 0.00 AC: 0 AN: 52698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34624

Middle Eastern (MID) AF: 0.000869 AC: 2 AN: 2302

European-Non Finnish (NFE) AF: 0.00000313 AC: 1 AN: 319122

Other (OTH) AF: 0.0000345 AC: 1 AN: 28988

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	-0.61
CADD	Benign	0.64
DANN	Benign	0.73
PhyloP100		-0.16

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: rs886056415; hg19: chr2-88857079;