chr5-176643254-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001099408.2(EIF4E1B):​c.188C>T​(p.Pro63Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EIF4E1B
NM_001099408.2 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.916
Variant links:
Genes affected
EIF4E1B (HGNC:33179): (eukaryotic translation initiation factor 4E family member 1B) Predicted to enable RNA 7-methylguanosine cap binding activity and translation initiation factor activity. Predicted to be involved in regulation of translation and translational initiation. Predicted to be located in cytoplasm. Predicted to be part of eukaryotic translation initiation factor 4F complex and mRNA cap binding activity complex. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EIF4E1BNM_001099408.2 linkc.188C>T p.Pro63Leu missense_variant Exon 4 of 9 ENST00000318682.11 NP_001092878.1 A6NMX2
EIF4E1BNM_001375362.1 linkc.188C>T p.Pro63Leu missense_variant Exon 4 of 9 NP_001362291.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EIF4E1BENST00000318682.11 linkc.188C>T p.Pro63Leu missense_variant Exon 4 of 9 5 NM_001099408.2 ENSP00000323714.6 A6NMX2
EIF4E1BENST00000504597.5 linkc.188C>T p.Pro63Leu missense_variant Exon 4 of 9 5 ENSP00000427633.1 A6NMX2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000806
AC:
2
AN:
248200
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134804
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000100
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.00000480
AC:
7
AN:
1459800
Hom.:
0
Cov.:
34
AF XY:
0.00000826
AC XY:
6
AN XY:
726156
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000312
Hom.:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.188C>T (p.P63L) alteration is located in exon 4 (coding exon 2) of the EIF4E1B gene. This alteration results from a C to T substitution at nucleotide position 188, causing the proline (P) at amino acid position 63 to be replaced by a leucine (L). 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
0.098
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
T;T;.;T
Eigen
Benign
-0.058
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.87
.;D;D;.
M_CAP
Benign
0.039
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
3.0
M;M;.;M
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-8.0
.;D;D;D
REVEL
Benign
0.21
Sift
Uncertain
0.0010
.;D;D;D
Sift4G
Uncertain
0.025
.;D;T;D
Polyphen
0.88
P;P;.;P
Vest4
0.26
MutPred
0.74
Loss of ubiquitination at K58 (P = 0.047);Loss of ubiquitination at K58 (P = 0.047);Loss of ubiquitination at K58 (P = 0.047);Loss of ubiquitination at K58 (P = 0.047);
MVP
0.63
MPC
0.33
ClinPred
0.58
D
GERP RS
2.9
Varity_R
0.26
gMVP
0.61

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: rs1329632376; hg19: chr5-176070255; API