chr1-44978366-G-A

Variant names:

• chr1-44978366-G-A
• rs11556200
• NM_020365.5:c.243C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020365.5(EIF2B3):​c.243C>T​(p.Asp81Asp) 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
• Publications: 31 publications found

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]

EIF2B3 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020365.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B3	NM_020365.5	MANE Select	c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 12	NP_065098.1
	EIF2B3	NM_001166588.3		c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 10	NP_001160060.1
	EIF2B3	NM_001261418.2		c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 11	NP_001248347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 12	ENSP00000353575.2
	EIF2B3	ENST00000372183.7	TSL:1	c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 10	ENSP00000361257.3
	EIF2B3	ENST00000620860.4	TSL:1	c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 11	ENSP00000483996.1

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

GnomAD2 exomes AF: 0.264 AC: 66428 AN: 251372 AF XY: 0.253

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 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

African (AFR) AF: 0.393 AC: 13136 AN: 33460

American (AMR) AF: 0.398 AC: 17809 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6184 AN: 26136

East Asian (EAS) AF: 0.253 AC: 10033 AN: 39686

South Asian (SAS) AF: 0.203 AC: 17528 AN: 86248

European-Finnish (FIN) AF: 0.223 AC: 11913 AN: 53314

Middle Eastern (MID) AF: 0.235 AC: 1358 AN: 5768

European-Non Finnish (NFE) AF: 0.242 AC: 269204 AN: 1111648

Other (OTH) AF: 0.261 AC: 15778 AN: 60382

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

African (AFR) AF: 0.386 AC: 15974 AN: 41408

American (AMR) AF: 0.352 AC: 5370 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 813 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1379 AN: 5158

South Asian (SAS) AF: 0.200 AC: 967 AN: 4828

European-Finnish (FIN) AF: 0.210 AC: 2209 AN: 10510

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16140 AN: 67978

Other (OTH) AF: 0.285 AC: 599 AN: 2104

Alfa AF: 0.256 Hom.: 8658

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 24, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Vanishing white matter disease Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.5
DANN	Benign	0.41
PhyloP100		-0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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