1-44850980-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020365.5(EIF2B3):​c.1330G>A​(p.Val444Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V444V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

EIF2B3
NM_020365.5 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.41144237).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EIF2B3NM_020365.5 linkc.1330G>A p.Val444Met missense_variant Exon 12 of 12 ENST00000360403.7 NP_065098.1 Q9NR50-1Q9HA31

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EIF2B3ENST00000360403.7 linkc.1330G>A p.Val444Met missense_variant Exon 12 of 12 1 NM_020365.5 ENSP00000353575.2 Q9NR50-1
EIF2B3ENST00000620860 linkc.*20G>A 3_prime_UTR_variant Exon 11 of 11 1 ENSP00000483996.1 Q9NR50-3
EIF2B3ENST00000439363 linkc.*20G>A 3_prime_UTR_variant Exon 7 of 7 3 ENSP00000396985.1 H0Y580

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251322
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135846
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:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461840
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000261
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000666
Hom.:
0
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1330G>A (p.V444M) alteration is located in exon 12 (coding exon 11) of the EIF2B3 gene. This alteration results from a G to A substitution at nucleotide position 1330, causing the valine (V) at amino acid position 444 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.075
D
BayesDel_noAF
Uncertain
0.0
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.13
T
Eigen
Benign
0.048
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.41
T
MetaSVM
Uncertain
0.087
D
MutationAssessor
Benign
1.3
L
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-1.0
N
REVEL
Uncertain
0.39
Sift
Benign
0.14
T
Sift4G
Benign
0.16
T
Polyphen
0.15
B
Vest4
0.58
MVP
0.93
MPC
0.30
ClinPred
0.41
T
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.17
gMVP
0.69

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

LitVar

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

Other links and lift over

dbSNP: rs374466099; hg19: chr1-45316652; API