Genetic Variant NM_001968.5:c.399+548A>G (chr4-98886531-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001968.5(EIF4E):c.399+548A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 426,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

EIF4E
NM_001968.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.792

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

autism, susceptibility to, 19
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

EIF4E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004441768).

BP6

Variant 4-98886531-T-C is Benign according to our data. Variant chr4-98886531-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 720923.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001968.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E	NM_001968.5	MANE Select	c.399+548A>G		intron	N/A	NP_001959.1	P06730-1
EIF4E	NM_001130679.3		c.415A>G	p.Met139Val	missense	Exon 6 of 8	NP_001124151.1	P06730-2
EIF4E	NM_001331017.2		c.483+548A>G		intron	N/A	NP_001317946.1	D6RBW1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4E	ENST00000450253.7	TSL:1 MANE Select	c.399+548A>G		intron	N/A	ENSP00000389624.2	P06730-1
EIF4E	ENST00000280892.10	TSL:1	c.459+548A>G		intron	N/A	ENSP00000280892.6	P06730-3
EIF4E	ENST00000505992.1	TSL:5	c.415A>G	p.Met139Val	missense	Exon 6 of 8	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes

AF:

0.00264

AC:

401

AN:

151656

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00790

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.000684

AC:

AN:

112498

AF XY:

0.000522

show subpopulations

Gnomad AFR exome

AF:

0.00774

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000162

Gnomad OTH exome

AF:

0.000870

GnomAD4 exome

AF:

0.000498

AC:

137

AN:

275150

Hom.:

Cov.:

AF XY:

0.000372

AC XY:

AN XY:

155812

show subpopulations

African (AFR)

AF:

0.00827

AC:

AN:

7494

American (AMR)

AF:

0.00122

AC:

AN:

24600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9500

East Asian (EAS)

AF:

0.00

AC:

AN:

8260

South Asian (SAS)

AF:

0.0000551

AC:

AN:

54456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

11654

Middle Eastern (MID)

AF:

0.000990

AC:

AN:

1010

European-Non Finnish (NFE)

AF:

0.000199

AC:

AN:

145434

Other (OTH)

AF:

0.000942

AC:

AN:

12742

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00266

AC:

403

AN:

151774

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

188

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.00793

AC:

328

AN:

41374

American (AMR)

AF:

0.00223

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00690

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67928

Other (OTH)

AF:

0.00522

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000857

Hom.:

Bravo

AF:

0.00320

ExAC

AF:

0.000324

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

6.8

(source)

DANN

Benign

0.33

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.0

PhyloP100

-0.79

PROVEAN

Benign

-0.020

REVEL

Benign

0.025

Sift

Uncertain

0.029

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.12

MutPred

0.56

Loss of solvent accessibility (P = 0.0249)

MVP

0.33

MPC

1.1

ClinPred

0.022

GERP RS

-1.8

gMVP

0.72

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over