Genetic Variant EIF4E1B:p.Gly213Ser (chr5-176645888-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001099408.2(EIF4E1B):c.637G>A(p.Gly213Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EIF4E1B
NM_001099408.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.38

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4087435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2 link	c.637G>A	p.Gly213Ser	missense_variant	Exon 9 of 9	ENST00000318682.11	NP_001092878.1	A6NMX2
EIF4E1B	NM_001375362.1 link	c.637G>A	p.Gly213Ser	missense_variant	Exon 9 of 9		NP_001362291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E1B	ENST00000318682.11 link	c.637G>A	p.Gly213Ser	missense_variant	Exon 9 of 9	5	NM_001099408.2	ENSP00000323714.6		A6NMX2
EIF4E1B	ENST00000504597.5 link	c.637G>A	p.Gly213Ser	missense_variant	Exon 9 of 9	5		ENSP00000427633.1		A6NMX2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.90e-7

AC:

AN:

1450262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720474

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33134

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

42910

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25876

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39000

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

84274

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

52634

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1106738

Gnomad4 Remaining exome

AF:

0.0000167

AC:

AN:

59944

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.0000656

AC:

0.0000655824

AN:

0.0000655824

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.637G>A (p.G213S) alteration is located in exon 9 (coding exon 7) of the EIF4E1B gene. This alteration results from a G to A substitution at nucleotide position 637, causing the glycine (G) at amino acid position 213 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

0.17

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D;.

M_CAP

Benign

0.024

MetaRNN

Benign

0.41

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.2

.;D;D

REVEL

Benign

0.12

Sift

Benign

0.21

.;T;T

Sift4G

Benign

0.18

.;T;T

Polyphen

0.43

B;B;B

Vest4

0.49, 0.49

MutPred

0.24

Loss of catalytic residue at L214 (P = 0.0923);Loss of catalytic residue at L214 (P = 0.0923);Loss of catalytic residue at L214 (P = 0.0923);

MVP

0.63

MPC

0.78

ClinPred

0.97

GERP RS

5.2

Varity_R

0.37

gMVP

0.48

Mutation Taster

=41/59

disease causing

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

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