rs7602534

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001034116.2(EIF2B4):​c.76-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,406 control chromosomes in the GnomAD database, including 125,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13164 hom., cov: 32)
Exomes 𝑓: 0.39 ( 111864 hom. )

Consequence

EIF2B4
NM_001034116.2 splice_region, intron

Scores

2
Splicing: ADA: 0.0003890
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.28

Publications

42 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 Gene-Disease associations (from GenCC):
  • leukoencephalopathy with vanishing white matter 4
    Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
  • 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.37).
BP6
Variant 2-27369556-C-T is Benign according to our data. Variant chr2-27369556-C-T is described in ClinVar as [Benign]. Clinvar id is 95738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.477 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EIF2B4NM_001034116.2 linkc.76-7G>A splice_region_variant, intron_variant Intron 2 of 12 ENST00000347454.9 NP_001029288.1 Q9UI10-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EIF2B4ENST00000347454.9 linkc.76-7G>A splice_region_variant, intron_variant Intron 2 of 12 1 NM_001034116.2 ENSP00000233552.6 Q9UI10-1

Frequencies

GnomAD3 genomes
AF:
0.408
AC:
61985
AN:
151866
Hom.:
13131
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.483
Gnomad AMI
AF:
0.220
Gnomad AMR
AF:
0.449
Gnomad ASJ
AF:
0.329
Gnomad EAS
AF:
0.149
Gnomad SAS
AF:
0.402
Gnomad FIN
AF:
0.429
Gnomad MID
AF:
0.363
Gnomad NFE
AF:
0.379
Gnomad OTH
AF:
0.371
GnomAD2 exomes
AF:
0.398
AC:
100015
AN:
251384
AF XY:
0.391
show subpopulations
Gnomad AFR exome
AF:
0.483
Gnomad AMR exome
AF:
0.553
Gnomad ASJ exome
AF:
0.333
Gnomad EAS exome
AF:
0.147
Gnomad FIN exome
AF:
0.428
Gnomad NFE exome
AF:
0.379
Gnomad OTH exome
AF:
0.387
GnomAD4 exome
AF:
0.386
AC:
564162
AN:
1461422
Hom.:
111864
Cov.:
47
AF XY:
0.385
AC XY:
279597
AN XY:
727030
show subpopulations
African (AFR)
AF:
0.485
AC:
16226
AN:
33470
American (AMR)
AF:
0.543
AC:
24286
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.333
AC:
8700
AN:
26134
East Asian (EAS)
AF:
0.131
AC:
5205
AN:
39662
South Asian (SAS)
AF:
0.397
AC:
34202
AN:
86256
European-Finnish (FIN)
AF:
0.432
AC:
23016
AN:
53330
Middle Eastern (MID)
AF:
0.337
AC:
1943
AN:
5768
European-Non Finnish (NFE)
AF:
0.385
AC:
427977
AN:
1111690
Other (OTH)
AF:
0.374
AC:
22607
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.464
Heterozygous variant carriers
0
20617
41235
61852
82470
103087
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
13622
27244
40866
54488
68110
<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:
0.408
AC:
62074
AN:
151984
Hom.:
13164
Cov.:
32
AF XY:
0.408
AC XY:
30333
AN XY:
74304
show subpopulations
African (AFR)
AF:
0.483
AC:
19990
AN:
41424
American (AMR)
AF:
0.450
AC:
6866
AN:
15266
Ashkenazi Jewish (ASJ)
AF:
0.329
AC:
1141
AN:
3468
East Asian (EAS)
AF:
0.150
AC:
774
AN:
5170
South Asian (SAS)
AF:
0.403
AC:
1938
AN:
4812
European-Finnish (FIN)
AF:
0.429
AC:
4526
AN:
10560
Middle Eastern (MID)
AF:
0.370
AC:
108
AN:
292
European-Non Finnish (NFE)
AF:
0.379
AC:
25736
AN:
67964
Other (OTH)
AF:
0.375
AC:
794
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
1855
3711
5566
7422
9277
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
576
1152
1728
2304
2880
<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:
0.386
Hom.:
52560
Bravo
AF:
0.414
Asia WGS
AF:
0.339
AC:
1179
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Sep 26, 2019
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28008009) -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 13, 2017
Athena Diagnostics
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:2
Dec 19, 2014
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Vanishing white matter disease Benign:2
Jan 13, 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. -

Jul 30, 2021
Genome-Nilou Lab
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
-0.37
CADD
Benign
14
DANN
Benign
0.87
PhyloP100
1.3
PromoterAI
-0.016
Neutral
Mutation Taster
=100/0
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00039
dbscSNV1_RF
Benign
0.042
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

Other links and lift over

dbSNP: rs7602534; hg19: chr2-27592423; COSMIC: COSV52009209; COSMIC: COSV52009209; API