4-98881149-GAAA-GAAAAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001968.5(EIF4E):​c.540-10_540-8dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,141,726 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: EIF4E NM_001968.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.94
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E	NM_001968.5	MANE Select	c.540-10_540-8dupTTT		splice_region intron	N/A	NP_001959.1	P06730-1
	EIF4E	NM_001130679.3		c.633-10_633-8dupTTT		splice_region intron	N/A	NP_001124151.1	P06730-2
	EIF4E	NM_001331017.2		c.624-10_624-8dupTTT		splice_region intron	N/A	NP_001317946.1	D6RBW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E	ENST00000450253.7	TSL:1 MANE Select	c.540-8_540-7insTTT		splice_region intron	N/A	ENSP00000389624.2	P06730-1
	EIF4E	ENST00000280892.10	TSL:1	c.600-8_600-7insTTT		splice_region intron	N/A	ENSP00000280892.6	P06730-3
	EIF4E	ENST00000505992.1	TSL:5	c.633-8_633-7insTTT		splice_region intron	N/A	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000754 AC: 7 AN: 92850 AF XY: 0.0000607

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000310

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 15 AN: 1141726 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 7 AN XY: 566568

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000375 AC: 1 AN: 26662

American (AMR) AF: 0.00 AC: 0 AN: 31884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19184

East Asian (EAS) AF: 0.0000706 AC: 2 AN: 28330

South Asian (SAS) AF: 0.0000314 AC: 2 AN: 63750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4698

European-Non Finnish (NFE) AF: 0.0000102 AC: 9 AN: 881092

Other (OTH) AF: 0.0000216 AC: 1 AN: 46342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

Splicing

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

Other links and lift over

dbSNP: rs374891583; hg19: chr4-99802300;