1-44986555-G-C

Position:

• chr1-44986555-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020365.5(EIF2B3):​c.-72C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 152,278 control chromosomes in the GnomAD database, including 18,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (18304 hom., cov: 33)
  • Exomes 𝑓: 0.41 (24 hom.)
• Consequence: EIF2B3 NM_020365.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.50

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-44986555-G-C is Benign according to our data. Variant chr1-44986555-G-C is described in ClinVar as [Benign]. Clinvar id is 297453.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B3	NM_020365.5	c.-72C>G		5_prime_UTR_variant	1/12	ENST00000360403.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B3	ENST00000360403.7	c.-72C>G		5_prime_UTR_variant	1/12	1	NM_020365.5	P1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72725 AN: 151906 Hom.: 18278 Cov.: 33

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.409 AC: 104 AN: 254 Hom.: 24 Cov.: 0 AF XY: 0.403 AC XY: 83 AN XY: 206

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.625

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.479 AC: 72810 AN: 152024 Hom.: 18304 Cov.: 33 AF XY: 0.475 AC XY: 35307 AN XY: 74306

Gnomad4 AFR AF: 0.629

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.400

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.438

Alfa AF: 0.312 Hom.: 791

Bravo AF: 0.498

Asia WGS AF: 0.400 AC: 1390 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vanishing white matter disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.23
DANN	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs489676; hg19: chr1-45452227;