3-71693926-C-G

Position:

• chr3-71693926-C-G

Variant summary

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

The NM_001134651.2(EIF4E3):​c.421G>C​(p.Glu141Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EIF4E3 NM_001134651.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

Genes affected

EIF4E3 (HGNC:31837): (eukaryotic translation initiation factor 4E family member 3) EIF4E3 belongs to the EIF4E family of translational initiation factors that interact with the 5-prime cap structure of mRNA and recruit mRNA to the ribosome (Joshi et al., 2004 [PubMed 15153109]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4E3	NM_001134651.2	c.421G>C	p.Glu141Gln	missense_variant	5/7	ENST00000425534.8	NP_001128123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4E3	ENST00000425534.8	c.421G>C	p.Glu141Gln	missense_variant	5/7	2	NM_001134651.2	ENSP00000393324	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431292 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 709500

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: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

May 13, 2024

The c.421G>C (p.E141Q) alteration is located in exon 5 (coding exon 5) of the EIF4E3 gene. This alteration results from a G to C substitution at nucleotide position 421, causing the glutamic acid (E) at amino acid position 141 to be replaced by a glutamine (Q). 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	0.67
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.;.;T;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;D;D;.;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.60		Gain of MoRF binding (P = 0.0342);.;.;.;.;.;.;.;
MVP		0.78
MPC		0.21
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.52
gMVP		0.63

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: chr3-71743077;