chr4-98891271-T-C

Position:

• chr4-98891271-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001968.5(EIF4E):​c.187A>G​(p.Ile63Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, EIF4E
• BP4: Computational evidence support a benign effect (MetaRNN=0.23146468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4E	NM_001968.5	c.187A>G	p.Ile63Val	missense_variant	3/7	ENST00000450253.7
EIF4E	NM_001130679.3	c.187A>G	p.Ile63Val	missense_variant	3/8
EIF4E	NM_001331017.2	c.271A>G	p.Ile91Val	missense_variant	4/8
EIF4E	NM_001130678.4	c.247A>G	p.Ile83Val	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4E	ENST00000450253.7	c.187A>G	p.Ile63Val	missense_variant	3/7	1	NM_001968.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.187A>G (p.I63V) alteration is located in exon 3 (coding exon 3) of the EIF4E gene. This alteration results from a A to G substitution at nucleotide position 187, causing the isoleucine (I) at amino acid position 63 to be replaced by a valine (V). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.058
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.22	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.61	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;.;.;B
Vest4		0.31
MutPred		0.53		Gain of ubiquitination at K65 (P = 0.0913);.;.;Gain of ubiquitination at K65 (P = 0.0913);
MVP		0.69
MPC		1.0
ClinPred		0.90	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-99812422;