1-20807491-C-T

Variant summary

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

The NM_001391906.1(EIF4G3):​c.4754G>A​(p.Arg1585Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,583,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

EIF4G3
NM_001391906.1 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.15
Variant links:
Genes affected
EIF4G3 (HGNC:3298): (eukaryotic translation initiation factor 4 gamma 3) The protein encoded by this gene is thought to be part of the eIF4F protein complex, which is involved in mRNA cap recognition and transport of mRNAs to the ribosome. Interestingly, a microRNA (miR-520c-3p) has been found that negatively regulates synthesis of the encoded protein, and this leads to a global decrease in protein translation and cell proliferation. Therefore, this protein is a key component of the anti-tumor activity of miR-520c-3p. [provided by RefSeq, May 2016]

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
EIF4G3NM_001391906.1 linkc.4754G>A p.Arg1585Gln missense_variant Exon 37 of 37 ENST00000602326.6 NP_001378835.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EIF4G3ENST00000602326.6 linkc.4754G>A p.Arg1585Gln missense_variant Exon 37 of 37 1 NM_001391906.1 ENSP00000473510.2 A0A8J9G7U8

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.00000412
AC:
1
AN:
242564
Hom.:
0
AF XY:
0.00000761
AC XY:
1
AN XY:
131368
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000348
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000769
AC:
11
AN:
1431336
Hom.:
0
Cov.:
30
AF XY:
0.00000847
AC XY:
6
AN XY:
708782
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:
0.0000122
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000916
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152088
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000480

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.4694G>A (p.R1565Q) alteration is located in exon 35 (coding exon 31) of the EIF4G3 gene. This alteration results from a G to A substitution at nucleotide position 4694, causing the arginine (R) at amino acid position 1565 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
0.91
BayesDel_addAF
Uncertain
0.055
T
BayesDel_noAF
Benign
-0.16
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.60
.;D;.;T;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D
M_CAP
Benign
0.072
D
MetaRNN
Uncertain
0.70
D;D;D;D;D
MetaSVM
Uncertain
-0.050
T
MutationAssessor
Benign
1.7
.;L;.;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.9
D;D;.;.;.
REVEL
Uncertain
0.52
Sift
Benign
0.15
T;T;.;.;.
Sift4G
Benign
0.11
T;T;T;T;D
Polyphen
1.0
.;D;.;.;.
Vest4
0.73
MutPred
0.59
.;Gain of catalytic residue at D1533 (P = 0.4187);.;.;.;
MVP
0.78
MPC
1.6
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.24
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1282632284; hg19: chr1-21133984; API