2-232550743-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004846.4(EIF4E2):c.19G>A(p.Ala7Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EIF4E2 NM_004846.4 missense, splice_region
• Scores: Splicing: ADA: 0.9366
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.42

Genes affected

EIF4E2 (HGNC:3293): (eukaryotic translation initiation factor 4E family member 2) Enables ubiquitin protein ligase binding activity. Involved in positive regulation of miRNA mediated inhibition of translation. Acts upstream of or within negative regulation of translation. Located in P-body. Part of mRNA cap binding activity complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.21598783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4E2	NM_004846.4	c.19G>A	p.Ala7Thr	missense_variant, splice_region_variant	1/7	ENST00000258416.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4E2	ENST00000258416.8	c.19G>A	p.Ala7Thr	missense_variant, splice_region_variant	1/7	1	NM_004846.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430942 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709794

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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

Dec 16, 2023

The c.19G>A (p.A7T) alteration is located in exon 1 (coding exon 1) of the EIF4E2 gene. This alteration results from a G to A substitution at nucleotide position 19, causing the alanine (A) at amino acid position 7 to be replaced by a threonine (T). 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	Pathogenic	0.86
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.035	T;.;.;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.10	T;T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T
Polyphen		0.38	B;P;.;.;P;.;.
Vest4		0.41
MutPred		0.15		Gain of phosphorylation at A7 (P = 0.0153);Gain of phosphorylation at A7 (P = 0.0153);Gain of phosphorylation at A7 (P = 0.0153);Gain of phosphorylation at A7 (P = 0.0153);Gain of phosphorylation at A7 (P = 0.0153);Gain of phosphorylation at A7 (P = 0.0153);Gain of phosphorylation at A7 (P = 0.0153);
MVP		0.35
MPC		0.90
ClinPred		0.91	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.59
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

LitVar

Other links and lift over

dbSNP: rs1692275723; hg19: chr2-233415453;