rs263978

chr1-44897320-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020365.5(EIF2B3):c.656+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,458,560 control chromosomes in the GnomAD database, including 270,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (37153 hom., cov: 33)
  • Exomes 𝑓: 0.59 (233700 hom.)
• Consequence: EIF2B3 NM_020365.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-44897320-T-C is Benign according to our data. Variant chr1-44897320-T-C is described in ClinVar as [Benign]. Clinvar id is 261222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF2B3	NM_020365.5	c.656+35A>G		intron_variant		ENST00000360403.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF2B3	ENST00000360403.7	c.656+35A>G		intron_variant		1	NM_020365.5	P1
EIF2B3	ENST00000372183.7	c.656+35A>G		intron_variant		1
EIF2B3	ENST00000620860.4	c.656+35A>G		intron_variant		1
EIF2B3	ENST00000439363.5	c.118+35A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.678 AC: 103142 AN: 152050 Hom.: 37076 Cov.: 33

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.639

GnomAD3 exomes AF: 0.649 AC: 156822 AN: 241798 Hom.: 53519 AF XY: 0.633 AC XY: 82626 AN XY: 130474

Gnomad AFR exome AF: 0.908

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.564

Gnomad EAS exome AF: 0.974

Gnomad SAS exome AF: 0.653

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.547

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.588 AC: 768363 AN: 1306392 Hom.: 233700 Cov.: 18 AF XY: 0.587 AC XY: 385987 AN XY: 657710

Gnomad4 AFR exome AF: 0.915

Gnomad4 AMR exome AF: 0.778

Gnomad4 ASJ exome AF: 0.560

Gnomad4 EAS exome AF: 0.983

Gnomad4 SAS exome AF: 0.650

Gnomad4 FIN exome AF: 0.536

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.610

GnomAD4 genome AF: 0.679 AC: 103283 AN: 152168 Hom.: 37153 Cov.: 33 AF XY: 0.680 AC XY: 50548 AN XY: 74382

Gnomad4 AFR AF: 0.904

Gnomad4 AMR AF: 0.709

Gnomad4 ASJ AF: 0.556

Gnomad4 EAS AF: 0.975

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.515

Gnomad4 NFE AF: 0.550

Gnomad4 OTH AF: 0.644

Alfa AF: 0.626 Hom.: 8558

Bravo AF: 0.702

Asia WGS AF: 0.852 AC: 2958 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.2
Dann	Benign	0.21

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: rs263978; hg19: chr1-45362992;