Variant chr1-20817520-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001391906.1(EIF4G3):c.4387T>G(p.Ser1463Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,600,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1463C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 1 hom. )

Consequence

EIF4G3
NM_001391906.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.28

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]

EIF4G3 links:

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ACMG classification

Classification made for transcript

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=0.10701683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4G3	NM_001391906.1 linkuse as main transcript	c.4387T>G	p.Ser1463Ala	missense_variant	34/37	ENST00000602326.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4G3	ENST00000602326.6 linkuse as main transcript	c.4387T>G	p.Ser1463Ala	missense_variant	34/37	1	NM_001391906.1	A2

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151602

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

GnomAD3 exomes

AF:

0.0000524

AC:

AN:

248214

Hom.:

AF XY:

0.0000819

AC XY:

AN XY:

134386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.00000967

AC:

AN:

1448414

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

720498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000204

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:

0.00000181

Gnomad4 OTH exome

AF:

0.0000503

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151602

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74034

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

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:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.4327T>G (p.S1443A) alteration is located in exon 32 (coding exon 28) of the EIF4G3 gene. This alteration results from a T to G substitution at nucleotide position 4327, causing the serine (S) at amino acid position 1443 to be replaced by an alanine (A). 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

0.070

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

.;T;.;T;T

Eigen

Benign

0.030

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.1

N;N;.;.;.

REVEL

Benign

0.064

Sift

Uncertain

0.023

D;T;.;.;.

Sift4G

Uncertain

0.059

T;T;T;T;D

Polyphen

0.014

.;B;.;.;.

Vest4

0.55

MutPred

0.26

.;Loss of phosphorylation at S1407 (P = 0.0197);.;.;.;

MVP

0.49

MPC

0.56

ClinPred

0.12

GERP RS

5.4

Varity_R

0.067

gMVP

0.32

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over