rs11556200

Positions:

• chr1-44978366-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020365.5(EIF2B3):​c.243C>T​(p.Asp81=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,288 control chromosomes in the GnomAD database, including 53,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6841 hom., cov: 32)
  • Exomes 𝑓: 0.25 (46589 hom.)
• Consequence: EIF2B3 NM_020365.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.603

Genes affected

EIF2B3 (HGNC:3259): (eukaryotic translation initiation factor 2B subunit gamma) The protein encoded by this gene is one of the subunits of initiation factor eIF2B, which catalyzes the exchange of eukaryotic initiation factor 2-bound GDP for GTP. It has also been found to function as a cofactor of hepatitis C virus internal ribosome entry site-mediated translation. Mutations in this gene have been associated with leukodystrophy with vanishing white matter. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-44978366-G-A is Benign according to our data. Variant chr1-44978366-G-A is described in ClinVar as [Benign]. Clinvar id is 95947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.603 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.243C>T	p.Asp81=	synonymous_variant	3/12	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.243C>T	p.Asp81=	synonymous_variant	3/12	1	NM_020365.5	ENSP00000353575	P1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43674 AN: 151808 Hom.: 6831 Cov.: 32

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.201

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.288

GnomAD3 exomes AF: 0.264 AC: 66428 AN: 251372 Hom.: 9609 AF XY: 0.253 AC XY: 34365 AN XY: 135874

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.260

Gnomad SAS exome AF: 0.203

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.248 AC: 362943 AN: 1461362 Hom.: 46589 Cov.: 35 AF XY: 0.245 AC XY: 178271 AN XY: 727022

Gnomad4 AFR exome AF: 0.393

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.288 AC: 43700 AN: 151926 Hom.: 6841 Cov.: 32 AF XY: 0.285 AC XY: 21126 AN XY: 74226

Gnomad4 AFR AF: 0.386

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.210

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.285

Alfa AF: 0.250 Hom.: 6686

Bravo AF: 0.303

Asia WGS AF: 0.242 AC: 843 AN: 3478

EpiCase AF: 0.225

EpiControl AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 06, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Vanishing white matter disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.5
DANN	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs11556200; hg19: chr1-45444038; COSMIC: COSV64517510;