NM_020365.5:c.656+2740A>C

Variant names:

• chr1-44894615-T-G
• rs263977
• NM_020365.5:c.656+2740A>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.656+2740A>C 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 151,930 control chromosomes in the GnomAD database, including 15,024 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 (15024 hom., cov: 31)
• Consequence: EIF2B3 NM_020365.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 9 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.656+2740A>C		intron_variant	Intron 6 of 11	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.656+2740A>C		intron_variant	Intron 6 of 11	1	NM_020365.5	ENSP00000353575.2
EIF2B3	ENST00000372183.7	c.656+2740A>C		intron_variant	Intron 6 of 9	1		ENSP00000361257.3
EIF2B3	ENST00000620860.4	c.656+2740A>C		intron_variant	Intron 6 of 10	1		ENSP00000483996.1
EIF2B3	ENST00000439363.5	c.116+2740A>C		intron_variant	Intron 2 of 6	3		ENSP00000396985.1

Frequencies

GnomAD3 genomes AF: 0.431 AC: 65417 AN: 151812 Hom.: 14989 Cov.: 31

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.431 AC: 65507 AN: 151930 Hom.: 15024 Cov.: 31 AF XY: 0.430 AC XY: 31928 AN XY: 74276

African (AFR) AF: 0.590 AC: 24449 AN: 41438

American (AMR) AF: 0.468 AC: 7135 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1113 AN: 3468

East Asian (EAS) AF: 0.446 AC: 2304 AN: 5166

South Asian (SAS) AF: 0.343 AC: 1655 AN: 4828

European-Finnish (FIN) AF: 0.338 AC: 3566 AN: 10550

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.356 AC: 24160 AN: 67930

Other (OTH) AF: 0.378 AC: 798 AN: 2110

Alfa AF: 0.419 Hom.: 2895

Bravo AF: 0.449

Asia WGS AF: 0.380 AC: 1321 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.6
DANN	Benign	0.84
PhyloP100		0.0
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: rs263977; hg19: chr1-45360287;