rs7571971

Variant names:

• chr2-88595833-T-C
• rs7571971
• ENST00000415570.1:n.25A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000415570.1(EIF2AK3):​n.25A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 723,880 control chromosomes in the GnomAD database, including 191,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45999 hom., cov: 31)
  • Exomes 𝑓: 0.71 (145015 hom.)
• Consequence: EIF2AK3 ENST00000415570.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.64
• Publications: 61 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-88595833-T-C is Benign according to our data. Variant chr2-88595833-T-C is described in ClinVar as Benign. ClinVar VariationId is 1174990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.937 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2AK3	NM_004836.7	c.439-170A>G		intron_variant	Intron 2 of 16	ENST00000303236.9	NP_004827.4
EIF2AK3	NM_001313915.2	c.-15-170A>G		intron_variant	Intron 2 of 16		NP_001300844.1
EIF2AK3	XM_047446428.1	c.148-170A>G		intron_variant	Intron 2 of 16		XP_047302384.1
EIF2AK3	XM_047446430.1	c.439-170A>G		intron_variant	Intron 2 of 11		XP_047302386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2AK3	ENST00000303236.9	c.439-170A>G		intron_variant	Intron 2 of 16	1	NM_004836.7	ENSP00000307235.3

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116673 AN: 151920 Hom.: 45947 Cov.: 31

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.685

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.752

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.723

GnomAD2 exomes AF: 0.697 AC: 94622 AN: 135836 AF XY: 0.689

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.687

Gnomad ASJ exome AF: 0.781

Gnomad EAS exome AF: 0.508

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.691

GnomAD4 exome AF: 0.708 AC: 404680 AN: 571842 Hom.: 145015 Cov.: 6 AF XY: 0.704 AC XY: 216948 AN XY: 308378

African (AFR) AF: 0.942 AC: 14978 AN: 15894

American (AMR) AF: 0.685 AC: 23080 AN: 33702

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 15287 AN: 19842

East Asian (EAS) AF: 0.553 AC: 17611 AN: 31834

South Asian (SAS) AF: 0.623 AC: 38469 AN: 61720

European-Finnish (FIN) AF: 0.660 AC: 22143 AN: 33568

Middle Eastern (MID) AF: 0.738 AC: 3000 AN: 4066

European-Non Finnish (NFE) AF: 0.728 AC: 247679 AN: 340184

Other (OTH) AF: 0.723 AC: 22433 AN: 31032

GnomAD4 genome AF: 0.768 AC: 116780 AN: 152038 Hom.: 45999 Cov.: 31 AF XY: 0.759 AC XY: 56400 AN XY: 74302

African (AFR) AF: 0.945 AC: 39196 AN: 41498

American (AMR) AF: 0.685 AC: 10459 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2719 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2713 AN: 5152

South Asian (SAS) AF: 0.615 AC: 2954 AN: 4800

European-Finnish (FIN) AF: 0.652 AC: 6879 AN: 10558

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.728 AC: 49512 AN: 67986

Other (OTH) AF: 0.721 AC: 1521 AN: 2110

Alfa AF: 0.736 Hom.: 119117

Bravo AF: 0.780

Asia WGS AF: 0.631 AC: 2196 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.7
DANN	Benign	0.48
PhyloP100		-1.6
PromoterAI		0.0088	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7571971; hg19: chr2-88895351; COSMIC: COSV57548123; COSMIC: COSV57548123;