1-44985805-C-T

Variant names:

• chr1-44985805-C-T
• rs364482
• NM_020365.5:c.-10+688G>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.-10+688G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,128 control chromosomes in the GnomAD database, including 5,860 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 0.24 (5860 hom., cov: 32)
• Consequence: EIF2B3 NM_020365.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.501
• Publications: 8 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.-10+688G>A		intron_variant	Intron 1 of 11	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.-10+688G>A		intron_variant	Intron 1 of 11	1	NM_020365.5	ENSP00000353575.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36579 AN: 152008 Hom.: 5848 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.243

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

GnomAD4 genome AF: 0.241 AC: 36622 AN: 152128 Hom.: 5860 Cov.: 32 AF XY: 0.240 AC XY: 17811 AN XY: 74366

African (AFR) AF: 0.432 AC: 17885 AN: 41446

American (AMR) AF: 0.314 AC: 4801 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3470

East Asian (EAS) AF: 0.275 AC: 1425 AN: 5174

South Asian (SAS) AF: 0.166 AC: 801 AN: 4824

European-Finnish (FIN) AF: 0.108 AC: 1145 AN: 10606

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9205 AN: 67998

Other (OTH) AF: 0.241 AC: 509 AN: 2112

Alfa AF: 0.167 Hom.: 5049

Bravo AF: 0.266

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.50
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: rs364482; hg19: chr1-45451477;