4-98886531-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001968.5(EIF4E):c.399+548A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 426,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: EIF4E NM_001968.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.792

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004441768).
• BP6: Variant 4-98886531-T-C is Benign according to our data. Variant chr4-98886531-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 720923.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 401 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4E	NM_001968.5	c.399+548A>G		intron_variant		ENST00000450253.7
EIF4E	NM_001130679.3	c.415A>G	p.Met139Val	missense_variant	6/8
EIF4E	NM_001130678.4	c.459+548A>G		intron_variant
EIF4E	NM_001331017.2	c.483+548A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4E	ENST00000450253.7	c.399+548A>G		intron_variant		1	NM_001968.5	P1

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 151656 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00790

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.000684 AC: 77 AN: 112498 Hom.: 1 AF XY: 0.000522 AC XY: 32 AN XY: 61310

Gnomad AFR exome AF: 0.00774

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.000870

GnomAD4 exome AF: 0.000498 AC: 137 AN: 275150 Hom.: 1 Cov.: 0 AF XY: 0.000372 AC XY: 58 AN XY: 155812

Gnomad4 AFR exome AF: 0.00827

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000551

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.000942

GnomAD4 genome AF: 0.00266 AC: 403 AN: 151774 Hom.: 0 Cov.: 32 AF XY: 0.00253 AC XY: 188 AN XY: 74166

Gnomad4 AFR AF: 0.00793

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.0000857 Hom.: 0

Bravo AF: 0.00320

ExAC AF: 0.000324 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	6.8
Dann	Benign	0.33
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.025
Sift	Uncertain	0.029	D
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.56		Loss of solvent accessibility (P = 0.0249);
MVP		0.33
MPC		1.1
ClinPred		0.022	T
GERP RS		-1.8
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201302296; hg19: chr4-99807682; COSMIC: COSV55189779; COSMIC: COSV55189779;