rs12498533

Variant names:

• chr4-98897682-A-C
• rs12498533
• NM_001968.5:c.125+4194T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-98897682-A-C
• chr4-98897682-A-G
• chr4-98897682-A-T

Variant summary

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

The NM_001968.5(EIF4E):​c.125+4194T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,092 control chromosomes in the GnomAD database, including 26,385 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 0.56 (26385 hom., cov: 33)
• Consequence: EIF4E NM_001968.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.746
• Publications: 7 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E	NM_001968.5	c.125+4194T>G		intron_variant	Intron 2 of 6	ENST00000450253.7	NP_001959.1
EIF4E	NM_001130679.3	c.125+4194T>G		intron_variant	Intron 2 of 7		NP_001124151.1
EIF4E	NM_001331017.2	c.209+4194T>G		intron_variant	Intron 3 of 7		NP_001317946.1
EIF4E	NM_001130678.4	c.185+4194T>G		intron_variant	Intron 2 of 6		NP_001124150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E	ENST00000450253.7	c.125+4194T>G		intron_variant	Intron 2 of 6	1	NM_001968.5	ENSP00000389624.2

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85136 AN: 151974 Hom.: 26322 Cov.: 33

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.561 AC: 85266 AN: 152092 Hom.: 26385 Cov.: 33 AF XY: 0.557 AC XY: 41407 AN XY: 74354

African (AFR) AF: 0.837 AC: 34713 AN: 41496

American (AMR) AF: 0.504 AC: 7700 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1741 AN: 3472

East Asian (EAS) AF: 0.686 AC: 3541 AN: 5164

South Asian (SAS) AF: 0.398 AC: 1919 AN: 4826

European-Finnish (FIN) AF: 0.451 AC: 4763 AN: 10560

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.430 AC: 29246 AN: 67982

Other (OTH) AF: 0.555 AC: 1168 AN: 2106

Alfa AF: 0.442 Hom.: 2628

Bravo AF: 0.582

Asia WGS AF: 0.526 AC: 1833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.29
DANN	Benign	0.46
PhyloP100		-0.75
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: rs12498533; hg19: chr4-99818833;