NM_001968.5:c.540-10_540-8delTTT

Variant names:

• chr4-98881149-GAAA-G
• rs374891583
• NM_001968.5:c.540-10_540-8delTTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001968.5(EIF4E):​c.540-10_540-8delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 1,141,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: EIF4E NM_001968.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.540-10_540-8delTTT		splice_region_variant, intron_variant	Intron 6 of 6	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.633-10_633-8delTTT		splice_region_variant, intron_variant	Intron 7 of 7		NP_001124151.1
EIF4E	NM_001331017.2	c.624-10_624-8delTTT		splice_region_variant, intron_variant	Intron 7 of 7		NP_001317946.1
EIF4E	NM_001130678.4	c.600-10_600-8delTTT		splice_region_variant, intron_variant	Intron 6 of 6		NP_001124150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7	c.540-10_540-8delTTT		splice_region_variant, intron_variant	Intron 6 of 6	1	NM_001968.5	ENSP00000389624.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000175 AC: 2 AN: 1141750 Hom.: 0 AF XY: 0.00000176 AC XY: 1 AN XY: 566578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

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;