4-98881149-GA-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001968.5(EIF4E):c.540-8del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.94

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]

ACMG classification

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 GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4E	NM_001968.5	c.540-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000450253.7
EIF4E	NM_001130678.4	c.600-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
EIF4E	NM_001130679.3	c.633-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
EIF4E	NM_001331017.2	c.624-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4E	ENST00000450253.7	c.540-8del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001968.5	P1

Frequencies

GnomAD3 genomes AF: 0.000656 AC: 80 AN: 122002 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.0613 AC XY: 3030 AN XY: 49430

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.: 1 Cov.: 31 AF XY: 0.0163 AC XY: 8062 AN XY: 494464

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: 80 AN: 122024 Hom.: 0 Cov.: 31 AF XY: 0.000768 AC XY: 45 AN XY: 58618

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

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs374891583; hg19: chr4-99802300;