dbSNP rs62323192: EIF4E:p.Asp125Asp (chr4-98887103-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BA1

The NM_001968.5(EIF4E):c.375C>T(p.Asp125Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.244 in 1,613,126 control chromosomes in the GnomAD database, including 52,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.19 ( 3677 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49001 hom. )

Consequence

EIF4E
NM_001968.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.11

Variant links:

Genes affected

EIF4E (HGNC:3287): (eukaryotic translation initiation factor 4E) The protein encoded by this gene is a component of the eukaryotic translation initiation factor 4F complex, which recognizes the 7-methylguanosine cap structure at the 5' end of messenger RNAs. The encoded protein aids in translation initiation by recruiting ribosomes to the 5'-cap structure. Association of this protein with the 4F complex is the rate-limiting step in translation initiation. This gene acts as a proto-oncogene, and its expression and activation is associated with transformation and tumorigenesis. Several pseudogenes of this gene are found on other chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

EIF4E links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 4-98887103-G-A is Benign according to our data. Variant chr4-98887103-G-A is described in ClinVar as [Benign]. Clinvar id is 3059002.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5 link	c.375C>T	p.Asp125Asp	synonymous_variant	Exon 5 of 7	ENST00000450253.7	NP_001959.1	P06730-1
EIF4E	NM_001130679.3 link	c.375C>T	p.Asp125Asp	synonymous_variant	Exon 5 of 8		NP_001124151.1	P06730-2
EIF4E	NM_001331017.2 link	c.459C>T	p.Asp153Asp	synonymous_variant	Exon 6 of 8		NP_001317946.1	P06730D6RBW1
EIF4E	NM_001130678.4 link	c.435C>T	p.Asp145Asp	synonymous_variant	Exon 5 of 7		NP_001124150.1	P06730-3Q32Q75X5D7E3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7 link	c.375C>T	p.Asp125Asp	synonymous_variant	Exon 5 of 7	1	NM_001968.5	ENSP00000389624.2		P06730-1

Frequencies

GnomAD3 genomes

AF:

0.191

AC:

28992

AN:

151986

Hom.:

3683

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0539

Gnomad AMI

AF:

0.319

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.155

Gnomad FIN

AF:

0.219

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.283

Gnomad OTH

AF:

0.209

GnomAD3 exomes

AF:

0.204

AC:

51131

AN:

251196

Hom.:

6490

AF XY:

0.212

AC XY:

28728

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0443

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.290

Gnomad EAS exome

AF:

0.00228

Gnomad SAS exome

AF:

0.166

Gnomad FIN exome

AF:

0.217

Gnomad NFE exome

AF:

0.282

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.250

AC:

364866

AN:

1461020

Hom.:

49001

Cov.:

AF XY:

0.249

AC XY:

181240

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.0452

Gnomad4 AMR exome

AF:

0.129

Gnomad4 ASJ exome

AF:

0.294

Gnomad4 EAS exome

AF:

0.00149

Gnomad4 SAS exome

AF:

0.165

Gnomad4 FIN exome

AF:

0.224

Gnomad4 NFE exome

AF:

0.277

Gnomad4 OTH exome

AF:

0.235

GnomAD4 genome

AF:

0.191

AC:

28992

AN:

152106

Hom.:

3677

Cov.:

AF XY:

0.185

AC XY:

13721

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0538

Gnomad4 AMR

AF:

0.175

Gnomad4 ASJ

AF:

0.290

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.155

Gnomad4 FIN

AF:

0.219

Gnomad4 NFE

AF:

0.283

Gnomad4 OTH

AF:

0.206

Alfa

AF:

0.247

Hom.:

2504

Bravo

AF:

0.181

Asia WGS

AF:

0.0830

AC:

290

AN:

3478

EpiCase

AF:

0.292

EpiControl

AF:

0.288

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

EIF4E-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

9.2

DANN

Benign

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over