chr4-98884959-T-A

Variant names:

• chr4-98884959-T-A
• NM_001968.5:c.502A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4E NM_001968.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13447031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.502A>T	p.Thr168Ser	missense_variant	Exon 6 of 7	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.595A>T	p.Thr199Ser	missense_variant	Exon 7 of 8		NP_001124151.1
EIF4E	NM_001331017.2	c.586A>T	p.Thr196Ser	missense_variant	Exon 7 of 8		NP_001317946.1
EIF4E	NM_001130678.4	c.562A>T	p.Thr188Ser	missense_variant	Exon 6 of 7		NP_001124150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7	c.502A>T	p.Thr168Ser	missense_variant	Exon 6 of 7	1	NM_001968.5	ENSP00000389624.2

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

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595A>T (p.T199S) alteration is located in exon 7 (coding exon 7) of the EIF4E gene. This alteration results from a A to T substitution at nucleotide position 595, causing the threonine (T) at amino acid position 199 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T;.;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.39	N;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.16
MutPred		0.45		Gain of disorder (P = 0.1543);.;.;.;
MVP		0.33
MPC		1.0
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.50

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: chr4-99806110;