rs35176330

Variant names:

• chr1-20941500-G-C
• rs35176330
• NM_001391906.1:c.1654C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. 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. 12/21 in silico tools predict 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
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 82 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G3	NM_001391906.1	c.1654C>G	p.Pro552Ala	missense_variant	Exon 14 of 37	ENST00000602326.6	NP_001378835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G3	ENST00000602326.6	c.1654C>G	p.Pro552Ala	missense_variant	Exon 14 of 37	1	NM_001391906.1	ENSP00000473510.2
EIF4G3	ENST00000356916.7	c.1519C>G	p.Pro507Ala	missense_variant	Exon 14 of 15	1		ENSP00000349386.3

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

GnomAD2 exomes AF: 0.0274 AC: 6766 AN: 246638 AF XY: 0.0289

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 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

African (AFR) AF: 0.00451 AC: 150 AN: 33250

American (AMR) AF: 0.0136 AC: 602 AN: 44138

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 841 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0151 AC: 1288 AN: 85476

European-Finnish (FIN) AF: 0.0593 AC: 3154 AN: 53170

Middle Eastern (MID) AF: 0.0286 AC: 164 AN: 5744

European-Non Finnish (NFE) AF: 0.0316 AC: 35049 AN: 1109652

Other (OTH) AF: 0.0275 AC: 1657 AN: 60164

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

African (AFR) AF: 0.00534 AC: 222 AN: 41558

American (AMR) AF: 0.0212 AC: 324 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4826

European-Finnish (FIN) AF: 0.0662 AC: 701 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0331 AC: 2248 AN: 68006

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

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;.;.;.;.
PhyloP100		4.1
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
Mutation Taster		=288/12	polymorphism (auto)

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