rs11556200

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:8
• 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 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

Sel.	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	Q9NR50-1
	EIF2B3	NM_001166588.3		c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 10	NP_001160060.1	Q9NR50-2
	EIF2B3	NM_001261418.2		c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 11	NP_001248347.1	Q9NR50-3

Ensembl Transcripts

Sel.	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	Q9NR50-1
	EIF2B3	ENST00000372183.7	TSL:1	c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 10	ENSP00000361257.3	Q9NR50-2
	EIF2B3	ENST00000620860.4	TSL:1	c.243C>T	p.Asp81Asp	synonymous	Exon 3 of 11	ENSP00000483996.1	Q9NR50-3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Vanishing white matter disease (1)

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;