chr3-184140122-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_003907.3(EIF2B5):​c.808G>A​(p.Asp270Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D270H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EIF2B5
NM_003907.3 missense

Scores

2
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.59
Variant links:
Genes affected
EIF2B5 (HGNC:3261): (eukaryotic translation initiation factor 2B subunit epsilon) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a helix (size 9) in uniprot entity EI2BE_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_003907.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-184140122-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 40178.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.35433176).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EIF2B5NM_003907.3 linkuse as main transcriptc.808G>A p.Asp270Asn missense_variant 6/16 ENST00000648915.2
EIF2B5XM_047449148.1 linkuse as main transcriptc.808G>A p.Asp270Asn missense_variant 6/11
EIF2B5XM_011513265.1 linkuse as main transcriptc.58G>A p.Asp20Asn missense_variant 2/12
EIF2B5XM_011513266.4 linkuse as main transcriptc.-94G>A 5_prime_UTR_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EIF2B5ENST00000648915.2 linkuse as main transcriptc.808G>A p.Asp270Asn missense_variant 6/16 NM_003907.3 P2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461706
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
0.0082
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
22
DANN
Benign
0.54
DEOGEN2
Benign
0.069
T;.;T
Eigen
Benign
0.050
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
.;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.35
T;T;T
MetaSVM
Uncertain
0.28
D
MutationAssessor
Benign
0.90
L;.;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.84
N;.;.
REVEL
Uncertain
0.41
Sift
Benign
0.87
T;.;.
Sift4G
Benign
0.89
T;.;.
Polyphen
0.0070
B;.;B
Vest4
0.33
MutPred
0.49
Gain of glycosylation at T268 (P = 0.0181);.;Gain of glycosylation at T268 (P = 0.0181);
MVP
0.67
MPC
0.29
ClinPred
0.37
T
GERP RS
5.9
Varity_R
0.25
gMVP
0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397514646; hg19: chr3-183857910; API