Genetic Variant EIF4E:c.540-8delT (chr4-98881149-GA-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001968.5(EIF4E):c.540-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,125,276 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.016 ( 1 hom. )

Consequence

EIF4E
NM_001968.5 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.94

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 -10 ACMG points.

BP6

Variant 4-98881149-GA-G is Benign according to our data. Variant chr4-98881149-GA-G is described in ClinVar as [Benign]. Clinvar id is 769289.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0155 (15562/1003252) while in subpopulation AMR AF= 0.0485 (1281/26404). AF 95% confidence interval is 0.0463. There are 1 homozygotes in gnomad4_exome. There are 8062 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5 link	c.540-8delT	splice_region_variant, intron_variant	Intron 6 of 6	ENST00000450253.7	NP_001959.1	P06730-1
EIF4E	NM_001130679.3 link	c.633-8delT	splice_region_variant, intron_variant	Intron 7 of 7		NP_001124151.1	P06730-2
EIF4E	NM_001331017.2 link	c.624-8delT	splice_region_variant, intron_variant	Intron 7 of 7		NP_001317946.1	P06730D6RBW1
EIF4E	NM_001130678.4 link	c.600-8delT	splice_region_variant, intron_variant	Intron 6 of 6		NP_001124150.1	P06730-3Q32Q75X5D7E3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7 link	c.540-8delT		splice_region_variant, intron_variant	Intron 6 of 6	1	NM_001968.5	ENSP00000389624.2		P06730-1

Frequencies

GnomAD3 genomes

AF:

0.000656

AC:

AN:

122002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000154

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000163

Gnomad ASJ

AF:

0.00304

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000500

Gnomad FIN

AF:

0.00285

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000708

Gnomad OTH

AF:

0.00175

GnomAD3 exomes

AF:

0.0607

AC:

5633

AN:

92850

Hom.:

AF XY:

0.0613

AC XY:

3030

AN XY:

49430

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.0823

Gnomad ASJ exome

AF:

0.0629

Gnomad EAS exome

AF:

0.0598

Gnomad SAS exome

AF:

0.0528

Gnomad FIN exome

AF:

0.0319

Gnomad NFE exome

AF:

0.0681

Gnomad OTH exome

AF:

0.0740

GnomAD4 exome

AF:

0.0155

AC:

15562

AN:

1003252

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

8062

AN XY:

494464

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.0485

Gnomad4 ASJ exome

AF:

0.0361

Gnomad4 EAS exome

AF:

0.0351

Gnomad4 SAS exome

AF:

0.0243

Gnomad4 FIN exome

AF:

0.0337

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.0220

GnomAD4 genome

AF:

0.000656

AC:

AN:

122024

Hom.:

Cov.:

AF XY:

0.000768

AC XY:

AN XY:

58618

show subpopulations

Gnomad4 AFR

AF:

0.000153

Gnomad4 AMR

AF:

0.000162

Gnomad4 ASJ

AF:

0.00304

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000502

Gnomad4 FIN

AF:

0.00285

Gnomad4 NFE

AF:

0.000708

Gnomad4 OTH

AF:

0.00174

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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