rs745875029

Variant names:

• chr2-232564271-A-G
• rs745875029
• NM_004846.4:c.295A>G

Variant summary

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

The NM_004846.4(EIF4E2):​c.295A>G​(p.Ser99Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,598,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: EIF4E2 NM_004846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

Genes affected

EIF4E2 (HGNC:3293): (eukaryotic translation initiation factor 4E family member 2) Enables ubiquitin protein ligase binding activity. Involved in positive regulation of miRNA mediated inhibition of translation. Acts upstream of or within negative regulation of translation. Located in P-body. Part of mRNA cap binding activity complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004846.4. 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
	EIF4E2	NM_004846.4	MANE Select	c.295A>G	p.Ser99Gly	missense	Exon 4 of 7	NP_004837.1	O60573-1
	EIF4E2	NM_001330202.2		c.280A>G	p.Ser94Gly	missense	Exon 4 of 7	NP_001317131.1
	EIF4E2	NM_001282958.2		c.295A>G	p.Ser99Gly	missense	Exon 4 of 8	NP_001269887.1	B8ZZ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E2	ENST00000258416.8	TSL:1 MANE Select	c.295A>G	p.Ser99Gly	missense	Exon 4 of 7	ENSP00000258416.3	O60573-1
	EIF4E2	ENST00000409098.5	TSL:1	c.295A>G	p.Ser99Gly	missense	Exon 4 of 7	ENSP00000386996.1	O60573-2
	EIF4E2	ENST00000690794.1		c.-6A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	ENSP00000509248.1	A0A8I5KT16

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 227670 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000505

Gnomad NFE exome AF: 0.0000297

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 38 AN: 1446232 Hom.: 0 Cov.: 31 AF XY: 0.0000209 AC XY: 15 AN XY: 717420

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 42972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25726

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 83298

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000326 AC: 36 AN: 1103310

Other (OTH) AF: 0.0000167 AC: 1 AN: 59810

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000825 AC: 1

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	Uncertain	0.45
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.043	D
Polyphen		0.28	B
Vest4		0.73
MutPred		0.59		Loss of stability (P = 0.0465)
MVP		0.49
MPC		0.99
ClinPred		0.61	D
GERP RS		5.7
Varity_R		0.70
gMVP		0.48
Mutation Taster		=36/64	disease causing

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: rs745875029; hg19: chr2-233428981;