1-44986555-G-C

Variant names:

• chr1-44986555-G-C
• rs489676
• NM_020365.5:c.-72C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000360403.7(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 ENST00000360403.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.50
• Publications: 7 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

ENSG00000300507 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 297453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360403.7. 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.-72C>G		5_prime_UTR	Exon 1 of 12	NP_065098.1
	EIF2B3	NM_001166588.3		c.-72C>G		5_prime_UTR	Exon 1 of 10	NP_001160060.1
	EIF2B3	NM_001261418.2		c.-72C>G		5_prime_UTR	Exon 1 of 11	NP_001248347.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.-72C>G		5_prime_UTR	Exon 1 of 12	ENSP00000353575.2
	EIF2B3	ENST00000372183.7	TSL:1	c.-72C>G		5_prime_UTR	Exon 1 of 10	ENSP00000361257.3
	EIF2B3	ENST00000620860.4	TSL:1	c.-72C>G		5_prime_UTR	Exon 1 of 11	ENSP00000483996.1

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

African (AFR) AF: 0.500 AC: 4 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.625 AC: 5 AN: 8

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AF: 0.500 AC: 3 AN: 6

European-Non Finnish (NFE) AF: 0.403 AC: 83 AN: 206

Other (OTH) AF: 0.500 AC: 7 AN: 14

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

African (AFR) AF: 0.629 AC: 26115 AN: 41502

American (AMR) AF: 0.516 AC: 7884 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1389 AN: 3472

East Asian (EAS) AF: 0.439 AC: 2261 AN: 5156

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4818

European-Finnish (FIN) AF: 0.363 AC: 3837 AN: 10562

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28198 AN: 67922

Other (OTH) AF: 0.438 AC: 925 AN: 2112

Alfa AF: 0.312 Hom.: 791

Bravo AF: 0.498

Asia WGS AF: 0.400 AC: 1390 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.23
DANN	Benign	0.45
PhyloP100		-3.5
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs489676; hg19: chr1-45452227;