1-20827652-G-T

Variant names:

• chr1-20827652-G-T
• rs760958641
• NM_001391906.1:c.4234C>A

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.4234C>A​(p.Leu1412Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EIF4G3 NM_001391906.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• 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=0.18290433).

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.4234C>A	p.Leu1412Ile	missense	Exon 32 of 37	NP_001378835.1	A0A8J9G7U8
	EIF4G3	NM_001391907.1		c.4324C>A	p.Leu1442Ile	missense	Exon 32 of 37	NP_001378836.1
	EIF4G3	NM_001438678.1		c.4213C>A	p.Leu1405Ile	missense	Exon 31 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.4234C>A	p.Leu1412Ile	missense	Exon 32 of 37	ENSP00000473510.2	A0A8J9G7U8
	EIF4G3	ENST00000400422.6	TSL:1	c.4174C>A	p.Leu1392Ile	missense	Exon 30 of 35	ENSP00000383274.2	A0A0A0MSA7
	EIF4G3	ENST00000693470.1		c.4996C>A	p.Leu1666Ile	missense	Exon 28 of 33	ENSP00000509295.1	A0A8I5KV92

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460184 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726436

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

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110810

Other (OTH) AF: 0.00 AC: 0 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000613 Hom.: 0

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	0.11
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.032
Sift	Benign	0.10	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.38
MVP		0.33
MPC		0.69
ClinPred		0.69	D
GERP RS		4.6
Varity_R		0.094
gMVP		0.69
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760958641; hg19: chr1-21154145;