Genetic Variant EIF2B4:p.Pro243Pro (chr2-27367799-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001034116.2(EIF2B4):c.729G>A(p.Pro243Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 1,613,502 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 31 hom., cov: 32)

Exomes 𝑓: 0.023 ( 421 hom. )

Consequence

EIF2B4
NM_001034116.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.381

Publications

12 publications found

Variant links:

Genes affected

EIF2B4 (HGNC:3260): (eukaryotic translation initiation factor 2B subunit delta) Eukaryotic initiation factor 2B (EIF2B), which is necessary for protein synthesis, is a GTP exchange factor composed of five different subunits. The protein encoded by this gene is the fourth, or delta, subunit. Defects in this gene are a cause of leukoencephalopathy with vanishing white matter (VWM) and ovarioleukodystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EIF2B4 links:

GTF3C2-AS2 (HGNC:55699): (GTF3C2 antisense RNA 2)

GTF3C2-AS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002826959).

BP6

Variant 2-27367799-C-T is Benign according to our data. Variant chr2-27367799-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.381 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0165 (2509/152140) while in subpopulation NFE AF = 0.0256 (1740/68006). AF 95% confidence interval is 0.0246. There are 31 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2B4	NM_001034116.2	MANE Select	c.729G>A	p.Pro243Pro	synonymous	Exon 8 of 13	NP_001029288.1
EIF2B4	NM_001318965.2		c.792G>A	p.Pro264Pro	synonymous	Exon 7 of 12	NP_001305894.1
EIF2B4	NM_172195.4		c.789G>A	p.Pro263Pro	synonymous	Exon 7 of 12	NP_751945.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EIF2B4	ENST00000347454.9	TSL:1 MANE Select	c.729G>A	p.Pro243Pro	synonymous	Exon 8 of 13	ENSP00000233552.6
EIF2B4	ENST00000451130.6	TSL:1	c.789G>A	p.Pro263Pro	synonymous	Exon 7 of 12	ENSP00000394869.2
EIF2B4	ENST00000445933.6	TSL:1	c.726G>A	p.Pro242Pro	synonymous	Exon 8 of 13	ENSP00000394397.2

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2512

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00474

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0318

Gnomad NFE

AF:

0.0256

Gnomad OTH

AF:

0.0240

GnomAD2 exomes

AF:

0.0169

AC:

4249

AN:

251454

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.0251

Gnomad OTH exome

AF:

0.0213

GnomAD4 exome

AF:

0.0227

AC:

33192

AN:

1461362

Hom.:

421

Cov.:

AF XY:

0.0224

AC XY:

16251

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.00424

AC:

142

AN:

33478

American (AMR)

AF:

0.0127

AC:

566

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0186

AC:

486

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00599

AC:

517

AN:

86254

European-Finnish (FIN)

AF:

0.0202

AC:

1078

AN:

53416

Middle Eastern (MID)

AF:

0.0234

AC:

135

AN:

5760

European-Non Finnish (NFE)

AF:

0.0261

AC:

28986

AN:

1111522

Other (OTH)

AF:

0.0212

AC:

1281

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

1640

3279

4919

6558

8198

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1054

2108

3162

4216

5270

<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:

0.0165

AC:

2509

AN:

152140

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1190

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00472

AC:

196

AN:

41488

American (AMR)

AF:

0.0141

AC:

215

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00290

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0186

AC:

197

AN:

10580

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0256

AC:

1740

AN:

68006

Other (OTH)

AF:

0.0237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

245

367

490

612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.0215

Hom.:

Bravo

AF:

0.0163

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0262

AC:

101

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.0248

AC:

213

ExAC

AF:

0.0169

AC:

2050

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0262

EpiControl

AF:

0.0240

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

0.20

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.1

(source)

DANN

Benign

0.71

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0028

PhyloP100

-0.38

Vest4

0.15

GERP RS

-7.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over