NM_001968.5:c.125+4194T>C

Variant names:

• chr4-98897682-A-G
• rs12498533
• NM_001968.5:c.125+4194T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001968.5(EIF4E):​c.125+4194T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EIF4E NM_001968.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.746
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.125+4194T>C		intron_variant	Intron 2 of 6	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.125+4194T>C		intron_variant	Intron 2 of 7		NP_001124151.1
EIF4E	NM_001331017.2	c.209+4194T>C		intron_variant	Intron 3 of 7		NP_001317946.1
EIF4E	NM_001130678.4	c.185+4194T>C		intron_variant	Intron 2 of 6		NP_001124150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7	c.125+4194T>C		intron_variant	Intron 2 of 6	1	NM_001968.5	ENSP00000389624.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.32
DANN	Benign	0.81
PhyloP100		-0.75

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

Other links and lift over

dbSNP: rs12498533; hg19: chr4-99818833;