rs263978

Variant names:

• chr1-44897320-T-C
• rs263978
• NM_020365.5:c.656+35A>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -1.40
• Publications: 13 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 -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 VariationId 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 rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.656+35A>G		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+35A>G		intron_variant	Intron 6 of 11	1	NM_020365.5	ENSP00000353575.2
EIF2B3	ENST00000372183.7	c.656+35A>G		intron_variant	Intron 6 of 9	1		ENSP00000361257.3
EIF2B3	ENST00000620860.4	c.656+35A>G		intron_variant	Intron 6 of 10	1		ENSP00000483996.1
EIF2B3	ENST00000439363.5	c.116+35A>G		intron_variant	Intron 2 of 6	3		ENSP00000396985.1

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

GnomAD2 exomes AF: 0.649 AC: 156822 AN: 241798 AF XY: 0.633

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 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

African (AFR) AF: 0.915 AC: 27963 AN: 30572

American (AMR) AF: 0.778 AC: 34093 AN: 43798

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 14019 AN: 25042

East Asian (EAS) AF: 0.983 AC: 38341 AN: 38988

South Asian (SAS) AF: 0.650 AC: 53443 AN: 82168

European-Finnish (FIN) AF: 0.536 AC: 28148 AN: 52552

Middle Eastern (MID) AF: 0.534 AC: 2938 AN: 5498

European-Non Finnish (NFE) AF: 0.551 AC: 535768 AN: 972586

Other (OTH) AF: 0.610 AC: 33650 AN: 55188

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

African (AFR) AF: 0.904 AC: 37541 AN: 41528

American (AMR) AF: 0.709 AC: 10842 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1928 AN: 3468

East Asian (EAS) AF: 0.975 AC: 5068 AN: 5196

South Asian (SAS) AF: 0.662 AC: 3194 AN: 4824

European-Finnish (FIN) AF: 0.515 AC: 5433 AN: 10554

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37370 AN: 67990

Other (OTH) AF: 0.644 AC: 1360 AN: 2112

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.21
PhyloP100		-1.4
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: rs263978; hg19: chr1-45362992;