Genetic Variant ENSG00000285708:c.-548G>A (chr3-71690138-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The ENST00000647725.1(ENSG00000285708):c.-548G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,460,940 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: 6.8e-7 ( 0 hom. )

Consequence

ENSG00000285708
ENST00000647725.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.69

Variant links:

Genes affected

ENSG00000285708 (HGNC:):

ENSG00000285708 links:

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]

EIF4E3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
EIF4E3	NM_001134651.2 link	c.500G>A	p.Ser167Asn	missense_variant	Exon 6 of 7	ENST00000425534.8	NP_001128123.1	Q8N5X7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000285708	ENST00000647725.1 link	c.-548G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 6 of 26			ENSP00000497585.1
EIF4E3	ENST00000425534.8 link	c.500G>A	p.Ser167Asn	missense_variant	Exon 6 of 7	2	NM_001134651.2	ENSP00000393324.2	Q8N5X7-1
ENSG00000285708	ENST00000647725.1 link	c.-548G>A		5_prime_UTR_variant	Exon 6 of 26			ENSP00000497585.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460940

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726808

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500G>A (p.S167N) alteration is located in exon 6 (coding exon 6) of the EIF4E3 gene. This alteration results from a G to A substitution at nucleotide position 500, causing the serine (S) at amino acid position 167 to be replaced by an asparagine (N). 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

0.95

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.;.;.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;.;D;.;.;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.54

D;D;D;D;D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.7

L;.;.;.;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-2.2

N;D;D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Benign

0.062

T;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.72

MutPred

0.55

Loss of disorder (P = 0.1239);.;.;.;.;.;

MVP

0.71

MPC

2.3

ClinPred

0.83

GERP RS

5.5

Varity_R

0.45

gMVP

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over