ENST00000372183.7:c.1210T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000372183.7(EIF2B3):c.1210T>G(p.Ser404Ala) variant causes a missense 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. 13/17 in silico tools predict a benign outcome for this variant. 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
ENST00000372183.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.02

Publications

6 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 -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372183.7. 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.1202+8T>G		splice_region intron	N/A	NP_065098.1
EIF2B3	NM_001166588.3		c.1210T>G	p.Ser404Ala	missense	Exon 10 of 10	NP_001160060.1
EIF2B3	NM_001261418.2		c.1202+8T>G		splice_region intron	N/A	NP_001248347.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2B3	ENST00000372183.7	TSL:1	c.1210T>G	p.Ser404Ala	missense	Exon 10 of 10	ENSP00000361257.3
EIF2B3	ENST00000360403.7	TSL:1 MANE Select	c.1202+8T>G		splice_region intron	N/A	ENSP00000353575.2
EIF2B3	ENST00000620860.4	TSL:1	c.1202+8T>G		splice_region intron	N/A	ENSP00000483996.1

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2420

AN:

152062

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0166

AC XY:

12037

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00293

AC:

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:

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:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0159

AC:

17705

AN:

1111910

Other (OTH)

AF:

0.0188

AC:

1135

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1097

2195

3292

4390

5487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

702

1404

2106

2808

3510

<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:

0.0160

AC:

2428

AN:

152180

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1222

AN XY:

74410

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.0102

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.0263

AC:

279

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0153

AC:

1043

AN:

68010

Other (OTH)

AF:

0.0152

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

119

237

356

474

593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0143

Hom.:

Bravo

AF:

0.0175

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0149

AC:

128

ExAC

AF:

0.0191

AC:

2316

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0149

EpiControl

AF:

0.0124

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 (3)

not specified (2)

Vanishing white matter disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.0055

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.12

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.76

PhyloP100

2.0

PROVEAN

Benign

0.020

REVEL

Benign

0.10

Sift

Benign

0.96

Sift4G

Benign

0.86

Polyphen

0.0

Vest4

0.044

ClinPred

0.0037

GERP RS

2.5

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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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