chr1-44978464-T-C

Variant names:

• chr1-44978464-T-C
• rs72887005
• NM_020365.5:c.149-4A>G

Variant summary

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

The ENST00000360403.7(EIF2B3):​c.149-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,612,146 control chromosomes in the GnomAD database, including 2,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (1061 hom., cov: 31)
  • Exomes 𝑓: 0.0065 (976 hom.)
• Consequence: EIF2B3 ENST00000360403.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001279
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.96
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-44978464-T-C is Benign according to our data. Variant chr1-44978464-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360403.7. 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.149-4A>G		splice_region intron	N/A	NP_065098.1
	EIF2B3	NM_001166588.3		c.149-4A>G		splice_region intron	N/A	NP_001160060.1
	EIF2B3	NM_001261418.2		c.149-4A>G		splice_region intron	N/A	NP_001248347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.149-4A>G		splice_region intron	N/A	ENSP00000353575.2
	EIF2B3	ENST00000372183.7	TSL:1	c.149-4A>G		splice_region intron	N/A	ENSP00000361257.3
	EIF2B3	ENST00000620860.4	TSL:1	c.149-4A>G		splice_region intron	N/A	ENSP00000483996.1

Frequencies

GnomAD3 genomes AF: 0.0638 AC: 9673 AN: 151690 Hom.: 1062 Cov.: 31

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0480

GnomAD2 exomes AF: 0.0163 AC: 4066 AN: 250166 AF XY: 0.0120

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.00654 AC: 9556 AN: 1460342 Hom.: 976 Cov.: 32 AF XY: 0.00554 AC XY: 4026 AN XY: 726502

African (AFR) AF: 0.230 AC: 7695 AN: 33442

American (AMR) AF: 0.0125 AC: 557 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.000604 AC: 52 AN: 86150

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52222

Middle Eastern (MID) AF: 0.00745 AC: 43 AN: 5768

European-Non Finnish (NFE) AF: 0.000266 AC: 296 AN: 1111928

Other (OTH) AF: 0.0151 AC: 910 AN: 60372

GnomAD4 genome AF: 0.0637 AC: 9674 AN: 151804 Hom.: 1061 Cov.: 31 AF XY: 0.0616 AC XY: 4571 AN XY: 74164

African (AFR) AF: 0.221 AC: 9141 AN: 41294

American (AMR) AF: 0.0256 AC: 390 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 67998

Other (OTH) AF: 0.0475 AC: 100 AN: 2104

Alfa AF: 0.0295 Hom.: 312

Bravo AF: 0.0724

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	EIF2B3-related disorder (1)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.053
DANN	Benign	0.54
PhyloP100		-2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.0040
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: rs72887005; hg19: chr1-45444136;