4-98886531-T-A

Variant names:

• chr4-98886531-T-A
• rs201302296
• NM_001968.5:c.399+548A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130679.3(EIF4E):​c.415A>T​(p.Met139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000468 in 426,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M139V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: EIF4E NM_001130679.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.073277354).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130679.3. 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.399+548A>T		intron	N/A	NP_001959.1	P06730-1
	EIF4E	NM_001130679.3		c.415A>T	p.Met139Leu	missense	Exon 6 of 8	NP_001124151.1	P06730-2
	EIF4E	NM_001331017.2		c.483+548A>T		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.399+548A>T		intron	N/A	ENSP00000389624.2	P06730-1
	EIF4E	ENST00000280892.10	TSL:1	c.459+548A>T		intron	N/A	ENSP00000280892.6	P06730-3
	EIF4E	ENST00000505992.1	TSL:5	c.415A>T	p.Met139Leu	missense	Exon 6 of 8	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151656 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000363 AC: 1 AN: 275152 Hom.: 0 Cov.: 0 AF XY: 0.00000642 AC XY: 1 AN XY: 155812

African (AFR) AF: 0.000133 AC: 1 AN: 7496

American (AMR) AF: 0.00 AC: 0 AN: 24600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9500

East Asian (EAS) AF: 0.00 AC: 0 AN: 8260

South Asian (SAS) AF: 0.00 AC: 0 AN: 54456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1010

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 145434

Other (OTH) AF: 0.00 AC: 0 AN: 12742

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151774 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74166

African (AFR) AF: 0.0000242 AC: 1 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000648 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.48
DANN	Benign	0.23
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.79
PROVEAN	Benign	0.020	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.58		Loss of solvent accessibility (P = 0.0249)
MVP		0.39
MPC		1.1
ClinPred		0.069	T
GERP RS		-1.8
gMVP		0.71
Mutation Taster		=98/2	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: rs201302296; hg19: chr4-99807682;