Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_020365.5(EIF2B3):c.633C>T(p.Ile211Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,472 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I211I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 71 hom. )

Consequence

EIF2B3
NM_020365.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.478

Publications

1 publications found

Variant links:

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

EIF2B3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.046).

BP6

Variant 1-44897378-G-A is Benign according to our data. Variant chr1-44897378-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.478 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00106 (161/152284) while in subpopulation SAS AF = 0.0307 (148/4826). AF 95% confidence interval is 0.0266. There are 4 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020365.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2B3	NM_020365.5	MANE Select	c.633C>T	p.Ile211Ile	synonymous	Exon 6 of 12	NP_065098.1
EIF2B3	NM_001166588.3		c.633C>T	p.Ile211Ile	synonymous	Exon 6 of 10	NP_001160060.1
EIF2B3	NM_001261418.2		c.633C>T	p.Ile211Ile	synonymous	Exon 6 of 11	NP_001248347.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.633C>T	p.Ile211Ile	synonymous	Exon 6 of 12	ENSP00000353575.2
EIF2B3	ENST00000372183.7	TSL:1	c.633C>T	p.Ile211Ile	synonymous	Exon 6 of 10	ENSP00000361257.3
EIF2B3	ENST00000620860.4	TSL:1	c.633C>T	p.Ile211Ile	synonymous	Exon 6 of 11	ENSP00000483996.1

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

164

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0313

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00373

AC:

936

AN:

250930

AF XY:

0.00506

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00190

AC:

2777

AN:

1461188

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

2014

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33456

American (AMR)

AF:

0.0000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000766

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0294

AC:

2534

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000819

AC:

AN:

1111642

Other (OTH)

AF:

0.00196

AC:

118

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152284

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.0307

AC:

148

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.000246

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

5.8

(source)

DANN

Benign

0.61

PhyloP100

-0.48

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over