chr4-98929085-C-A

Variant names:

• chr4-98929085-C-A
• rs777025316
• ENST00000280892.10:c.-113G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001130678.4(EIF4E):​c.-113G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,583,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: EIF4E NM_001130678.4 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.37
• 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)

ENSG00000263923 (HGNC:):

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 (BayesDel_noAF=-0.15).
• BP6: Variant 4-98929085-C-A is Benign according to our data. Variant chr4-98929085-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3057066.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130678.4. 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.18+10G>T		intron	N/A	NP_001959.1	P06730-1
	EIF4E	NM_001130678.4		c.-113G>T		5_prime_UTR	Exon 1 of 7	NP_001124150.1	X5D7E3
	EIF4E	NM_001130679.3		c.18+10G>T		intron	N/A	NP_001124151.1	P06730-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4E	ENST00000280892.10	TSL:1	c.-113G>T		5_prime_UTR	Exon 1 of 7	ENSP00000280892.6	P06730-3
	EIF4E	ENST00000450253.7	TSL:1 MANE Select	c.18+10G>T		intron	N/A	ENSP00000389624.2	P06730-1
	EIF4E	ENST00000505992.1	TSL:5	c.18+10G>T		intron	N/A	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.0000351 AC: 7 AN: 199444 AF XY: 0.0000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1431018 Hom.: 0 Cov.: 34 AF XY: 0.00000141 AC XY: 1 AN XY: 708748

African (AFR) AF: 0.00 AC: 0 AN: 32748

American (AMR) AF: 0.000146 AC: 6 AN: 40976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25500

East Asian (EAS) AF: 0.00 AC: 0 AN: 38016

South Asian (SAS) AF: 0.00 AC: 0 AN: 81960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096396

Other (OTH) AF: 0.00 AC: 0 AN: 59118

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EIF4E-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.93
PhyloP100		1.4
PromoterAI		0.026	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777025316; hg19: chr4-99850236;