2-88557424-C-CTA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_004836.7(EIF2AK3):c.*311_*312insTA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 356,034 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (5 hom.)
• Consequence: EIF2AK3 NM_004836.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.564

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00611 (926/151544) while in subpopulation NFE AF= 0.00819 (555/67790). AF 95% confidence interval is 0.00762. There are 1 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2AK3	NM_004836.7	c.*311_*312insTA		3_prime_UTR_variant	17/17	ENST00000303236.9
LOC101928371	NR_110236.1	n.651-17078_651-17077dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.*311_*312insTA		3_prime_UTR_variant	17/17	1	NM_004836.7	P1
	ENST00000413234.1	n.651-17078_651-17077dup		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 926 AN: 151426 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00678

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00819

Gnomad OTH AF: 0.00867

GnomAD4 exome AF: 0.00776 AC: 1587 AN: 204490 Hom.: 5 Cov.: 0 AF XY: 0.00724 AC XY: 785 AN XY: 108466

Gnomad4 AFR exome AF: 0.00235

Gnomad4 AMR exome AF: 0.00747

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00188

Gnomad4 SAS exome AF: 0.00208

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.00967

Gnomad4 OTH exome AF: 0.00708

GnomAD4 genome AF: 0.00611 AC: 926 AN: 151544 Hom.: 1 Cov.: 32 AF XY: 0.00656 AC XY: 486 AN XY: 74048

Gnomad4 AFR AF: 0.00160

Gnomad4 AMR AF: 0.00677

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.00819

Gnomad4 OTH AF: 0.00858

Bravo AF: 0.00532

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wolcott-Rallison dysplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767645334; hg19: chr2-88856942;