rs35176330

chr1-20941500-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BS1 BS2

The NM_001391906.1(EIF4G3):c.1654C>G(p.Pro552Ala) variant causes a missense change. The variant allele was found at a frequency of 0.029 in 1,609,296 control chromosomes in the GnomAD database, including 803 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (82 hom., cov: 32)
  • Exomes 𝑓: 0.029 (721 hom.)
• Consequence: EIF4G3 NM_001391906.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06

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 Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EIF4G3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019055307).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0245 (3734/152258) while in subpopulation NFE AF= 0.0331 (2248/68006). AF 95% confidence interval is 0.0319. There are 82 homozygotes in gnomad4. There are 1937 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 82 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4G3	NM_001391906.1	c.1654C>G	p.Pro552Ala	missense_variant	14/37	ENST00000602326.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4G3	ENST00000602326.6	c.1654C>G	p.Pro552Ala	missense_variant	14/37	1	NM_001391906.1	A2

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3734 AN: 152140 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00536

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0274 AC: 6766 AN: 246638 Hom.: 147 AF XY: 0.0289 AC XY: 3852 AN XY: 133264

Gnomad AFR exome AF: 0.00536

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0144

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.0362

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0294 AC: 42905 AN: 1457038 Hom.: 721 Cov.: 32 AF XY: 0.0294 AC XY: 21273 AN XY: 724624

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.0326

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.0593

Gnomad4 NFE exome AF: 0.0316

Gnomad4 OTH exome AF: 0.0275

GnomAD4 genome AF: 0.0245 AC: 3734 AN: 152258 Hom.: 82 Cov.: 32 AF XY: 0.0260 AC XY: 1937 AN XY: 74446

Gnomad4 AFR AF: 0.00534

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0297 Hom.: 58

Bravo AF: 0.0207

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0320 AC: 275

ExAC AF: 0.0277 AC: 3358

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.33	T;.;T;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	D;.;.;.;.
REVEL	Benign	0.071
Sift	Uncertain	0.014	D;.;.;.;.
Sift4G	Uncertain	0.021	D;D;D;D;T
Polyphen		0.11	B;.;.;.;.
Vest4		0.21
MPC		0.17
ClinPred		0.033	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.15

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

Other links and lift over

dbSNP: rs35176330; hg19: chr1-21267993; COSMIC: COSV51688495; COSMIC: COSV51688495;