Genetic Variant NM_001968.5:c.502A>T (chr4-98884959-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001968.5(EIF4E):c.502A>T(p.Thr168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EIF4E
NM_001968.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13447031).

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.502A>T	p.Thr168Ser	missense	Exon 6 of 7	NP_001959.1	P06730-1
EIF4E	NM_001130679.3		c.595A>T	p.Thr199Ser	missense	Exon 7 of 8	NP_001124151.1	P06730-2
EIF4E	NM_001331017.2		c.586A>T	p.Thr196Ser	missense	Exon 7 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.502A>T	p.Thr168Ser	missense	Exon 6 of 7	ENSP00000389624.2	P06730-1
EIF4E	ENST00000280892.10	TSL:1	c.562A>T	p.Thr188Ser	missense	Exon 6 of 7	ENSP00000280892.6	P06730-3
EIF4E	ENST00000505992.1	TSL:5	c.595A>T	p.Thr199Ser	missense	Exon 7 of 8	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.23

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.55

M_CAP

Benign

0.0050

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.39

PhyloP100

3.2

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.34

REVEL

Benign

0.078

Sift

Benign

0.45

Sift4G

Benign

0.71

Polyphen

0.0

Vest4

0.16

MutPred

0.45

Gain of disorder (P = 0.1543)

MVP

0.33

MPC

1.0

ClinPred

0.69

GERP RS

5.0

Varity_R

0.19

gMVP

0.50

Mutation Taster

=69/31

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over