chr4-98928975-A-G

Variant names:

• chr4-98928975-A-G
• rs11723037
• ENST00000280892.10:c.-3T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001130678.4(EIF4E):​c.-3T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 1,573,108 control chromosomes in the GnomAD database, including 171,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.56 (26336 hom., cov: 32)
  • Exomes 𝑓: 0.44 (145061 hom.)
• Consequence: EIF4E NM_001130678.4 5_prime_UTR
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.04
• Publications: 19 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-98928975-A-G is Benign according to our data. Variant chr4-98928975-A-G is described in ClinVar as Benign. ClinVar VariationId is 3061014.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

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+120T>C		intron	N/A	NP_001959.1	P06730-1
	EIF4E	NM_001130678.4		c.-3T>C		5_prime_UTR	Exon 1 of 7	NP_001124150.1	X5D7E3
	EIF4E	NM_001130679.3		c.18+120T>C		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.-3T>C		5_prime_UTR	Exon 1 of 7	ENSP00000280892.6	P06730-3
	EIF4E	ENST00000450253.7	TSL:1 MANE Select	c.18+120T>C		intron	N/A	ENSP00000389624.2	P06730-1
	EIF4E	ENST00000505992.1	TSL:5	c.18+120T>C		intron	N/A	ENSP00000425561.1	P06730-2

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85023 AN: 151856 Hom.: 26276 Cov.: 32

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.467 AC: 86136 AN: 184418 AF XY: 0.457

Gnomad AFR exome AF: 0.837

Gnomad AMR exome AF: 0.476

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.672

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.416

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.444 AC: 630993 AN: 1421134 Hom.: 145061 Cov.: 60 AF XY: 0.441 AC XY: 310194 AN XY: 703134

African (AFR) AF: 0.851 AC: 27521 AN: 32344

American (AMR) AF: 0.485 AC: 18687 AN: 38550

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 12701 AN: 25406

East Asian (EAS) AF: 0.689 AC: 25633 AN: 37180

South Asian (SAS) AF: 0.390 AC: 31640 AN: 81138

European-Finnish (FIN) AF: 0.439 AC: 22020 AN: 50172

Middle Eastern (MID) AF: 0.450 AC: 2570 AN: 5714

European-Non Finnish (NFE) AF: 0.423 AC: 462257 AN: 1091730

Other (OTH) AF: 0.475 AC: 27964 AN: 58900

GnomAD4 genome AF: 0.560 AC: 85151 AN: 151974 Hom.: 26336 Cov.: 32 AF XY: 0.556 AC XY: 41325 AN XY: 74262

African (AFR) AF: 0.836 AC: 34705 AN: 41504

American (AMR) AF: 0.503 AC: 7690 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1738 AN: 3466

East Asian (EAS) AF: 0.684 AC: 3499 AN: 5116

South Asian (SAS) AF: 0.398 AC: 1918 AN: 4820

European-Finnish (FIN) AF: 0.451 AC: 4763 AN: 10552

Middle Eastern (MID) AF: 0.442 AC: 129 AN: 292

European-Non Finnish (NFE) AF: 0.430 AC: 29196 AN: 67922

Other (OTH) AF: 0.555 AC: 1170 AN: 2110

Alfa AF: 0.480 Hom.: 80943

Bravo AF: 0.581

Asia WGS AF: 0.524 AC: 1826 AN: 3478

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	-0.55
CADD	Benign	17
DANN	Benign	0.67
PhyloP100		1.0
PromoterAI		-0.036	Neutral
Mutation Taster		=300/0	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: rs11723037; hg19: chr4-99850126; COSMIC: COSV55186293;