rs746307703

Variant names:

• chr1-20813209-G-A
• rs746307703
• NM_001391906.1:c.4546C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001391906.1(EIF4G3):​c.4546C>T​(p.Pro1516Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EIF4G3 NM_001391906.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14221162).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001391906.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4G3	NM_001391906.1	MANE Select	c.4546C>T	p.Pro1516Ser	missense	Exon 35 of 37	NP_001378835.1	A0A8J9G7U8
	EIF4G3	NM_001391907.1		c.4636C>T	p.Pro1546Ser	missense	Exon 35 of 37	NP_001378836.1
	EIF4G3	NM_001438678.1		c.4525C>T	p.Pro1509Ser	missense	Exon 34 of 36	NP_001425607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4G3	ENST00000602326.6	TSL:1 MANE Select	c.4546C>T	p.Pro1516Ser	missense	Exon 35 of 37	ENSP00000473510.2	A0A8J9G7U8
	EIF4G3	ENST00000400422.6	TSL:1	c.4486C>T	p.Pro1496Ser	missense	Exon 33 of 35	ENSP00000383274.2	A0A0A0MSA7
	EIF4G3	ENST00000693470.1		c.5308C>T	p.Pro1770Ser	missense	Exon 31 of 33	ENSP00000509295.1	A0A8I5KV92

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251278 AF XY: 0.0000294

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461504 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 727072

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111792

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000889026), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74306

African (AFR) AF: 0.000121 AC: 5 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.071	T
Eigen	Benign	0.015
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.32	N
PhyloP100		2.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.10
Sift	Benign	0.28	T
Sift4G	Benign	0.51	T
Polyphen		0.11	B
Vest4		0.23
MVP		0.13
MPC		0.65
ClinPred		0.13	T
GERP RS		5.9
Varity_R		0.065
gMVP		0.55
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs746307703; hg19: chr1-21139702;