chr8-108228329-A-C

Variant names:

• chr8-108228329-A-C
• rs1815556463
• NM_001568.3:c.660T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001568.3(EIF3E):​c.660T>G​(p.Phe220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EIF3E NM_001568.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.946
• Publications: 0 publications found

Genes affected

EIF3E (HGNC:3277): (eukaryotic translation initiation factor 3 subunit E) Enables protein N-terminus binding activity. Contributes to translation initiation factor activity. Involved in positive regulation of mRNA binding activity; regulation of gene expression; and translational initiation. Located in cytosol and nucleus. Part of eukaryotic translation initiation factor 3 complex. Colocalizes with PML body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001568.3. 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
	EIF3E	NM_001568.3	MANE Select	c.660T>G	p.Phe220Leu	missense	Exon 7 of 13	NP_001559.1	P60228

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF3E	ENST00000220849.10	TSL:1 MANE Select	c.660T>G	p.Phe220Leu	missense	Exon 7 of 13	ENSP00000220849.5	P60228
	EIF3E	ENST00000678042.1		c.660T>G	p.Phe220Leu	missense	Exon 7 of 14	ENSP00000503596.1	A0A7I2V3S3
	EIF3E	ENST00000677674.1		c.660T>G	p.Phe220Leu	missense	Exon 7 of 14	ENSP00000503434.1	A0A7I2V3I0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457116 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724900

African (AFR) AF: 0.00 AC: 0 AN: 33228

American (AMR) AF: 0.00 AC: 0 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.00 AC: 0 AN: 85666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5494

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109572

Other (OTH) AF: 0.00 AC: 0 AN: 60106

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.95
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.26
Sift	Benign	0.083	T
Sift4G	Uncertain	0.047	D
Polyphen		0.39	B
Vest4		0.85
MutPred		0.82		Loss of helix (P = 0.1299)
MVP		0.58
MPC		2.0
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.81
Mutation Taster		=21/79	disease causing

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: rs1815556463; hg19: chr8-109240558;