NM_001968.5:c.19-5235T>C

Variant names:

• chr4-98907217-A-G
• rs11727086
• NM_001968.5:c.19-5235T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001968.5(EIF4E):​c.19-5235T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 152,178 control chromosomes in the GnomAD database, including 3,675 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (3675 hom., cov: 32)
• Consequence: EIF4E NM_001968.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.600
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.19-5235T>C		intron_variant	Intron 1 of 6	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.19-5235T>C		intron_variant	Intron 1 of 7		NP_001124151.1
EIF4E	NM_001331017.2	c.102+2461T>C		intron_variant	Intron 2 of 7		NP_001317946.1
EIF4E	NM_001130678.4	c.79-5235T>C		intron_variant	Intron 1 of 6		NP_001124150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7	c.19-5235T>C		intron_variant	Intron 1 of 6	1	NM_001968.5	ENSP00000389624.2

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29004 AN: 152060 Hom.: 3681 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.208

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.191 AC: 29004 AN: 152178 Hom.: 3675 Cov.: 32 AF XY: 0.184 AC XY: 13724 AN XY: 74390

African (AFR) AF: 0.0538 AC: 2236 AN: 41550

American (AMR) AF: 0.175 AC: 2679 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1010 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5180

South Asian (SAS) AF: 0.156 AC: 752 AN: 4814

European-Finnish (FIN) AF: 0.219 AC: 2321 AN: 10592

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

European-Non Finnish (NFE) AF: 0.283 AC: 19205 AN: 67970

Other (OTH) AF: 0.206 AC: 435 AN: 2116

Alfa AF: 0.250 Hom.: 2673

Bravo AF: 0.181

Asia WGS AF: 0.0820 AC: 288 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.9
DANN	Benign	0.84
PhyloP100		0.60
Mutation Taster		=100/0	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: rs11727086; hg19: chr4-99828368;