Genetic Variant EIF4E1B:p.Pro63Leu (chr5-176643254-C-T) – ACMG Classification: Uncertain_significance (2 pts)

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

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]

EIF4E1B links:

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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
EIF4E1B	NM_001099408.2 link	c.188C>T	p.Pro63Leu	missense_variant	Exon 4 of 9	ENST00000318682.11	NP_001092878.1	A6NMX2
EIF4E1B	NM_001375362.1 link	c.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
EIF4E1B	ENST00000318682.11 link	c.188C>T	p.Pro63Leu	missense_variant	Exon 4 of 9	5	NM_001099408.2	ENSP00000323714.6		A6NMX2
EIF4E1B	ENST00000504597.5 link	c.188C>T	p.Pro63Leu	missense_variant	Exon 4 of 9	5		ENSP00000427633.1		A6NMX2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248200

Hom.:

AF XY:

0.0000148

AC XY:

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:

AN:

1459800

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

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.:

Alfa

AF:

0.0000312

Hom.:

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

BayesDel_noAF

Benign

-0.36

CADD

Benign

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

LIST_S2

Uncertain

0.87

.;D;D;.

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.72

D;D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.0

M;M;.;M

PrimateAI

Benign

0.41

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over