NM_001968.5:c.542G>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001968.5(EIF4E):c.542G>T(p.Arg181Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,608,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

EIF4E
NM_001968.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

Publications

1 publications found

Variant links:

Genes affected

EIF4E (HGNC:3287): (eukaryotic translation initiation factor 4E) The protein encoded by this gene is a component of the eukaryotic translation initiation factor 4F complex, which recognizes the 7-methylguanosine cap structure at the 5' end of messenger RNAs. The encoded protein aids in translation initiation by recruiting ribosomes to the 5'-cap structure. Association of this protein with the 4F complex is the rate-limiting step in translation initiation. This gene acts as a proto-oncogene, and its expression and activation is associated with transformation and tumorigenesis. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

EIF4E Gene-Disease associations (from GenCC):

autism, susceptibility to, 19
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

EIF4E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39753655).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001968.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E	NM_001968.5	MANE Select	c.542G>T	p.Arg181Met	missense splice_region	Exon 7 of 7	NP_001959.1	P06730-1
EIF4E	NM_001130679.3		c.635G>T	p.Arg212Met	missense splice_region	Exon 8 of 8	NP_001124151.1	P06730-2
EIF4E	NM_001331017.2		c.626G>T	p.Arg209Met	missense splice_region	Exon 8 of 8	NP_001317946.1	D6RBW1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E	ENST00000450253.7	TSL:1 MANE Select	c.542G>T	p.Arg181Met	missense splice_region	Exon 7 of 7	ENSP00000389624.2	P06730-1
EIF4E	ENST00000280892.10	TSL:1	c.602G>T	p.Arg201Met	missense splice_region	Exon 7 of 7	ENSP00000280892.6	P06730-3
EIF4E	ENST00000505992.1	TSL:5	c.635G>T	p.Arg212Met	missense splice_region	Exon 8 of 8	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000484

AC:

AN:

247760

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000889

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1459346

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

725864

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

44402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

85544

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000666

AC:

AN:

1111072

Other (OTH)

AF:

0.0000498

AC:

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

AF:

0.0000134

AC:

AN:

149294

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72768

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

39564

American (AMR)

AF:

0.00

AC:

AN:

15092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67856

Other (OTH)

AF:

0.00

AC:

AN:

2078

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000602

Hom.:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

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

Uncertain

0.44

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.024

MetaRNN

Benign

0.40

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

3.1

PhyloP100

2.9

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.28

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.012

Polyphen

0.63

Vest4

0.45

MutPred

0.50

Loss of MoRF binding (P = 0.0837)

MVP

0.46

MPC

1.5

ClinPred

0.39

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.80

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over