rs77068026

Variant names:

• chr1-44874670-A-C
• rs77068026
• ENST00000372183.7:c.1210T>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.1202+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,613,938 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (68 hom., cov: 32)
  • Exomes 𝑓: 0.017 (387 hom.)
• Consequence: EIF2B3 NM_020365.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.02
• Publications: 6 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 (MetaRNN=0.0020470321).
• BP6: Variant 1-44874670-A-C is Benign according to our data. Variant chr1-44874670-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 95945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF2B3	NM_020365.5	c.1202+8T>G		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000360403.7	NP_065098.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF2B3	ENST00000360403.7	c.1202+8T>G		splice_region_variant, intron_variant	Intron 10 of 11	1	NM_020365.5	ENSP00000353575.2

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2420 AN: 152062 Hom.: 68 Cov.: 32

Gnomad AFR AF: 0.00382

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0100

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0154

GnomAD2 exomes AF: 0.0218 AC: 5476 AN: 251400 AF XY: 0.0190

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0284

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0171 AC: 25013 AN: 1461758 Hom.: 387 Cov.: 32 AF XY: 0.0166 AC XY: 12037 AN XY: 727174

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.0781 AC: 3493 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 136 AN: 26134

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.00998 AC: 861 AN: 86248

European-Finnish (FIN) AF: 0.0291 AC: 1557 AN: 53418

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0159 AC: 17705 AN: 1111910

Other (OTH) AF: 0.0188 AC: 1135 AN: 60390

GnomAD4 genome AF: 0.0160 AC: 2428 AN: 152180 Hom.: 68 Cov.: 32 AF XY: 0.0164 AC XY: 1222 AN XY: 74410

African (AFR) AF: 0.00381 AC: 158 AN: 41524

American (AMR) AF: 0.0558 AC: 852 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4798

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1043 AN: 68010

Other (OTH) AF: 0.0152 AC: 32 AN: 2106

Alfa AF: 0.0143 Hom.: 42

Bravo AF: 0.0175

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0191 AC: 2316

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0149

EpiControl AF: 0.0124

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Oct 17, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Vanishing white matter disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Uncertain	0.98
Eigen	Benign	-0.0055
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.76	T
PhyloP100		2.0
PROVEAN	Benign	0.020	N
REVEL	Benign	0.10
Sift	Benign	0.96	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.044
ClinPred		0.0037	T
GERP RS		2.5
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77068026; hg19: chr1-45340342;