NM_001968.5:c.375C>T

Variant names:

• chr4-98887103-G-A
• rs62323192
• NM_001968.5:c.375C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BA1

The NM_001968.5(EIF4E):​c.375C>T​(p.Asp125Asp) variant causes a synonymous change. The variant allele was found at a frequency of 0.244 in 1,613,126 control chromosomes in the GnomAD database, including 52,678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (3677 hom., cov: 32)
  • Exomes 𝑓: 0.25 (49001 hom.)
• Consequence: EIF4E NM_001968.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.11
• Publications: 16 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.233).
• BP6: Variant 4-98887103-G-A is Benign according to our data. Variant chr4-98887103-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059002.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

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.375C>T	p.Asp125Asp	synonymous	Exon 5 of 7	NP_001959.1	P06730-1
	EIF4E	NM_001130679.3		c.375C>T	p.Asp125Asp	synonymous	Exon 5 of 8	NP_001124151.1	P06730-2
	EIF4E	NM_001331017.2		c.459C>T	p.Asp153Asp	synonymous	Exon 6 of 8	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.375C>T	p.Asp125Asp	synonymous	Exon 5 of 7	ENSP00000389624.2	P06730-1
	EIF4E	ENST00000280892.10	TSL:1	c.435C>T	p.Asp145Asp	synonymous	Exon 5 of 7	ENSP00000280892.6	P06730-3
	EIF4E	ENST00000505992.1	TSL:5	c.375C>T	p.Asp125Asp	synonymous	Exon 5 of 8	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes AF: 0.191 AC: 28992 AN: 151986 Hom.: 3683 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.204 AC: 51131 AN: 251196 AF XY: 0.212

Gnomad AFR exome AF: 0.0443

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.00228

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.282

Gnomad OTH exome AF: 0.236

GnomAD4 exome AF: 0.250 AC: 364866 AN: 1461020 Hom.: 49001 Cov.: 33 AF XY: 0.249 AC XY: 181240 AN XY: 726852

African (AFR) AF: 0.0452 AC: 1511 AN: 33464

American (AMR) AF: 0.129 AC: 5772 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 7690 AN: 26118

East Asian (EAS) AF: 0.00149 AC: 59 AN: 39674

South Asian (SAS) AF: 0.165 AC: 14211 AN: 86236

European-Finnish (FIN) AF: 0.224 AC: 11950 AN: 53398

Middle Eastern (MID) AF: 0.242 AC: 1321 AN: 5460

European-Non Finnish (NFE) AF: 0.277 AC: 308177 AN: 1111620

Other (OTH) AF: 0.235 AC: 14175 AN: 60338

GnomAD4 genome AF: 0.191 AC: 28992 AN: 152106 Hom.: 3677 Cov.: 32 AF XY: 0.185 AC XY: 13721 AN XY: 74368

African (AFR) AF: 0.0538 AC: 2235 AN: 41516

American (AMR) AF: 0.175 AC: 2681 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1005 AN: 3466

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5182

South Asian (SAS) AF: 0.155 AC: 748 AN: 4824

European-Finnish (FIN) AF: 0.219 AC: 2313 AN: 10558

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19210 AN: 67958

Other (OTH) AF: 0.206 AC: 434 AN: 2110

Alfa AF: 0.219 Hom.: 3281

Bravo AF: 0.181

Asia WGS AF: 0.0830 AC: 290 AN: 3478

EpiCase AF: 0.292

EpiControl AF: 0.288

ClinVar

ClinVar submissions

Significance: 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	-0.45
CADD	Benign	9.2
DANN	Benign	0.59
PhyloP100		4.1
Mutation Taster		=91/9	polymorphism (auto)

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: rs62323192; hg19: chr4-99808254; COSMIC: COSV55187106; COSMIC: COSV55187106;