rs263965

Variant names:

• chr1-44909853-C-T
• rs263965
• NM_020365.5:c.567-12409G>A

Variant summary

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

The NM_020365.5(EIF2B3):​c.567-12409G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 151,870 control chromosomes in the GnomAD database, including 14,971 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 0.43 (14971 hom., cov: 31)
• Consequence: EIF2B3 NM_020365.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.381
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.567-12409G>A		intron_variant	Intron 5 of 11	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.567-12409G>A		intron_variant	Intron 5 of 11	1	NM_020365.5	ENSP00000353575.2
EIF2B3	ENST00000372183.7	c.567-12409G>A		intron_variant	Intron 5 of 9	1		ENSP00000361257.3
EIF2B3	ENST00000620860.4	c.567-12409G>A		intron_variant	Intron 5 of 10	1		ENSP00000483996.1
EIF2B3	ENST00000439363.5	c.27-12409G>A		intron_variant	Intron 1 of 6	3		ENSP00000396985.1

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65310 AN: 151752 Hom.: 14942 Cov.: 31

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.466

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.383

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

GnomAD4 genome AF: 0.431 AC: 65393 AN: 151870 Hom.: 14971 Cov.: 31 AF XY: 0.429 AC XY: 31859 AN XY: 74208

African (AFR) AF: 0.589 AC: 24373 AN: 41388

American (AMR) AF: 0.467 AC: 7124 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1108 AN: 3466

East Asian (EAS) AF: 0.444 AC: 2293 AN: 5162

South Asian (SAS) AF: 0.343 AC: 1655 AN: 4822

European-Finnish (FIN) AF: 0.339 AC: 3572 AN: 10542

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24141 AN: 67926

Other (OTH) AF: 0.379 AC: 799 AN: 2110

Alfa AF: 0.422 Hom.: 1808

Bravo AF: 0.449

Asia WGS AF: 0.380 AC: 1323 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.48
PhyloP100		0.38
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: rs263965; hg19: chr1-45375525;