1-44965992-A-G

Variant names:

• chr1-44965992-A-G
• rs546354
• NM_020365.5:c.294+12323T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020365.5(EIF2B3):​c.294+12323T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 151,830 control chromosomes in the GnomAD database, including 6,072 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (6072 hom., cov: 29)
• Consequence: EIF2B3 NM_020365.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0420
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 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.294+12323T>C		intron	N/A	NP_065098.1
	EIF2B3	NM_001166588.3		c.294+12323T>C		intron	N/A	NP_001160060.1
	EIF2B3	NM_001261418.2		c.294+12323T>C		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.294+12323T>C		intron	N/A	ENSP00000353575.2
	EIF2B3	ENST00000372183.7	TSL:1	c.294+12323T>C		intron	N/A	ENSP00000361257.3
	EIF2B3	ENST00000620860.4	TSL:1	c.294+12323T>C		intron	N/A	ENSP00000483996.1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38242 AN: 151712 Hom.: 6058 Cov.: 29

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.205

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.252 AC: 38295 AN: 151830 Hom.: 6072 Cov.: 29 AF XY: 0.249 AC XY: 18481 AN XY: 74202

African (AFR) AF: 0.456 AC: 18844 AN: 41368

American (AMR) AF: 0.189 AC: 2880 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3464

East Asian (EAS) AF: 0.169 AC: 872 AN: 5150

South Asian (SAS) AF: 0.169 AC: 811 AN: 4808

European-Finnish (FIN) AF: 0.153 AC: 1614 AN: 10558

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.178 AC: 12102 AN: 67936

Other (OTH) AF: 0.203 AC: 427 AN: 2106

Alfa AF: 0.244 Hom.: 829

Bravo AF: 0.265

Asia WGS AF: 0.167 AC: 579 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.56
PhyloP100		-0.042
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: rs546354; hg19: chr1-45431664;