NM_001968.5:c.126-3048A>G

Variant names:

• chr4-98894380-T-C
• rs13109000
• NM_001968.5:c.126-3048A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001968.5(EIF4E):​c.126-3048A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 151,844 control chromosomes in the GnomAD database, including 4 homozygotes. 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: 𝑓 0.040 (4 hom., cov: 34)
• Consequence: EIF4E NM_001968.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.413
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS2: High Homozygotes in GnomAd4 at 4 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.126-3048A>G		intron_variant	Intron 2 of 6	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.126-3048A>G		intron_variant	Intron 2 of 7		NP_001124151.1
EIF4E	NM_001331017.2	c.210-3048A>G		intron_variant	Intron 3 of 7		NP_001317946.1
EIF4E	NM_001130678.4	c.186-3048A>G		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.126-3048A>G		intron_variant	Intron 2 of 6	1	NM_001968.5	ENSP00000389624.2

Frequencies

GnomAD3 genomes AF: 0.0401 AC: 6079 AN: 151726 Hom.: 4 Cov.: 34

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.0355

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0204

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0485

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

GnomAD4 genome AF: 0.0400 AC: 6077 AN: 151844 Hom.: 4 Cov.: 34 AF XY: 0.0372 AC XY: 2765 AN XY: 74276

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

African (AFR) AF: 0.0113 AC: 469 AN: 41556

American (AMR) AF: 0.0465 AC: 710 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3462

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4816

European-Finnish (FIN) AF: 0.0204 AC: 216 AN: 10590

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0639 AC: 4321 AN: 67672

Other (OTH) AF: 0.0480 AC: 101 AN: 2104

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0489 Hom.: 3

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	4.7
DANN	Benign	0.61
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism

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: rs13109000; hg19: chr4-99815531;