1-20817510-G-C

Variant names:

• chr1-20817510-G-C
• rs2061364839
• NM_001391906.1:c.4397C>G

Variant summary

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

The NM_001391906.1(EIF4G3):​c.4397C>G​(p.Pro1466Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P1466L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF4G3 NM_001391906.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.97

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]

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=0.13109994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G3	NM_001391906.1	c.4397C>G	p.Pro1466Arg	missense_variant	Exon 34 of 37	ENST00000602326.6	NP_001378835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G3	ENST00000602326.6	c.4397C>G	p.Pro1466Arg	missense_variant	Exon 34 of 37	1	NM_001391906.1	ENSP00000473510.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4337C>G (p.P1446R) alteration is located in exon 32 (coding exon 28) of the EIF4G3 gene. This alteration results from a C to G substitution at nucleotide position 4337, causing the proline (P) at amino acid position 1446 to be replaced by an arginine (R). 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	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T;.;T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	.;L;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.94	N;N;.;.;.
REVEL	Benign	0.078
Sift	Benign	0.037	D;T;.;.;.
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.0050	.;B;.;.;.
Vest4		0.39
MutPred		0.24		.;Loss of loop (P = 0.0374);.;.;.;
MVP		0.16
MPC		0.69
ClinPred		0.83	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2061364839; hg19: chr1-21144003;