Variant 5-176643639-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001099408.2(EIF4E1B):c.201G>C(p.Arg67Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,604,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

EIF4E1B
NM_001099408.2 missense, splice_region

Scores

Splicing: ADA: 0.8072

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.825

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3381306).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EIF4E1B	NM_001099408.2 linkuse as main transcript	c.201G>C	p.Arg67Ser	missense_variant, splice_region_variant	5/9	ENST00000318682.11
EIF4E1B	NM_001375362.1 linkuse as main transcript	c.201G>C	p.Arg67Ser	missense_variant, splice_region_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4E1B	ENST00000318682.11 linkuse as main transcript	c.201G>C	p.Arg67Ser	missense_variant, splice_region_variant	5/9	5	NM_001099408.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000345

AC:

AN:

231998

Hom.:

AF XY:

0.0000317

AC XY:

AN XY:

126004

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000765

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1452534

Hom.:

Cov.:

AF XY:

0.0000970

AC XY:

AN XY:

721566

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000142

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

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

Mar 01, 2023

The c.201G>C (p.R67S) alteration is located in exon 5 (coding exon 3) of the EIF4E1B gene. This alteration results from a G to C substitution at nucleotide position 201, causing the arginine (R) at amino acid position 67 to be replaced by a serine (S). 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

Benign

0.30

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;.;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.055

FATHMM_MKL

Uncertain

0.90

M_CAP

Benign

0.030

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.51

Polyphen

0.21

B;B;.;B

Vest4

0.45, 0.45

MutPred

0.51

Loss of MoRF binding (P = 0.016);Loss of MoRF binding (P = 0.016);Loss of MoRF binding (P = 0.016);Loss of MoRF binding (P = 0.016);

MVP

0.56

MPC

0.93

ClinPred

0.32

GERP RS

2.5

Varity_R

0.43

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.81

dbscSNV1_RF

Benign

0.64

SpliceAI score (max)

0.45

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.45

Position offset: 22

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