Variant 5-176645242-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001099408.2(EIF4E1B):c.473C>T(p.Thr158Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00158 in 1,597,586 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 4 hom. )

Consequence

EIF4E1B
NM_001099408.2 missense, splice_region

Scores

Splicing: ADA: 0.9935

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

EIF4E1B (HGNC:33179): (eukaryotic translation initiation factor 4E family member 1B) Predicted to enable RNA 7-methylguanosine cap binding activity and translation initiation factor activity. Predicted to be involved in regulation of translation and translational initiation. Predicted to be located in cytoplasm. Predicted to be part of eukaryotic translation initiation factor 4F complex and mRNA cap binding activity complex. [provided by Alliance of Genome Resources, Apr 2022]

EIF4E1B links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2 linkuse as main transcript	c.473C>T	p.Thr158Met	missense_variant, splice_region_variant	7/9	ENST00000318682.11	NP_001092878.1
EIF4E1B	NM_001375362.1 linkuse as main transcript	c.473C>T	p.Thr158Met	missense_variant, splice_region_variant	7/9		NP_001362291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4E1B	ENST00000318682.11 linkuse as main transcript	c.473C>T	p.Thr158Met	missense_variant, splice_region_variant	7/9	5	NM_001099408.2	ENSP00000323714	P1

Frequencies

GnomAD3 genomes

AF:

0.000934

AC:

142

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000837

AC:

183

AN:

218720

Hom.:

AF XY:

0.000815

AC XY:

AN XY:

119028

show subpopulations

Gnomad AFR exome

AF:

0.000317

Gnomad AMR exome

AF:

0.000263

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:

0.00172

Gnomad OTH exome

AF:

0.000728

GnomAD4 exome

AF:

0.00165

AC:

2384

AN:

1445408

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1134

AN XY:

717680

show subpopulations

Gnomad4 AFR exome

AF:

0.000181

Gnomad4 AMR exome

AF:

0.000217

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000386

Gnomad4 NFE exome

AF:

0.00209

Gnomad4 OTH exome

AF:

0.000903

GnomAD4 genome

AF:

0.000933

AC:

142

AN:

152178

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000386

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.000967

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000709

AC:

ESP6500EA

AF:

0.000949

AC:

ExAC

AF:

0.000654

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

The c.473C>T (p.T158M) alteration is located in exon 7 (coding exon 5) of the EIF4E1B gene. This alteration results from a C to T substitution at nucleotide position 473, causing the threonine (T) at amino acid position 158 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

.;D;.

M_CAP

Benign

0.066

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.0

M;M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.3

.;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.014

.;D;D

Sift4G

Uncertain

0.059

.;T;T

Polyphen

1.0

D;D;D

Vest4

0.73

MVP

0.77

MPC

0.90

ClinPred

0.085

GERP RS

5.8

Varity_R

0.16

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.79

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over