Genetic Variant EIF4E3:p.Arg14Leu (chr3-71725327-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001134651.2(EIF4E3):c.41G>T(p.Arg14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000097 in 824,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

EIF4E3
NM_001134651.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.05

Publications

0 publications found

Variant links:

Genes affected

EIF4E3 (HGNC:31837): (eukaryotic translation initiation factor 4E family member 3) EIF4E3 belongs to the EIF4E family of translational initiation factors that interact with the 5-prime cap structure of mRNA and recruit mRNA to the ribosome (Joshi et al., 2004 [PubMed 15153109]).[supplied by OMIM, Mar 2008]

EIF4E3 links:

ENSG00000285708 (HGNC:):

ENSG00000285708 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06728548).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134651.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E3	NM_001134651.2	MANE Select	c.41G>T	p.Arg14Leu	missense	Exon 1 of 7	NP_001128123.1	Q8N5X7-1
EIF4E3	NM_001134649.3		c.-143+3149G>T		intron	N/A	NP_001128121.1	Q8N5X7-2
EIF4E3	NM_001134650.1		c.-143+3149G>T		intron	N/A	NP_001128122.1	Q8N5X7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E3	ENST00000425534.8	TSL:2 MANE Select	c.41G>T	p.Arg14Leu	missense	Exon 1 of 7	ENSP00000393324.2	Q8N5X7-1
ENSG00000285708	ENST00000647725.1		c.-811+3149G>T		intron	N/A	ENSP00000497585.1
EIF4E3	ENST00000295612.7	TSL:1	c.-143+3149G>T		intron	N/A	ENSP00000295612.3	Q8N5X7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000970

AC:

AN:

824616

Hom.:

Cov.:

AF XY:

0.00000787

AC XY:

AN XY:

381172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15602

American (AMR)

AF:

0.00

AC:

AN:

1026

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5118

East Asian (EAS)

AF:

0.00

AC:

AN:

3608

South Asian (SAS)

AF:

0.00

AC:

AN:

17020

European-Finnish (FIN)

AF:

0.00

AC:

AN:

374

Middle Eastern (MID)

AF:

0.000620

AC:

AN:

1614

European-Non Finnish (NFE)

AF:

0.00000929

AC:

AN:

753280

Other (OTH)

AF:

0.00

AC:

AN:

26974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.024

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.40

M_CAP

Benign

0.032

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

1.4

REVEL

Benign

0.038

Sift

Benign

0.25

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.11

MutPred

0.48

Loss of solvent accessibility (P = 3e-04)

MVP

0.26

MPC

0.029

ClinPred

0.095

GERP RS

-1.7

PromoterAI

0.011

Neutral

(source)

Varity_R

0.058

gMVP

0.58

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over