Genetic Variant EIF4E1B:p.Ala195Val (chr5-176645486-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001099408.2(EIF4E1B):c.584C>T(p.Ala195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000641 in 1,513,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

EIF4E1B
NM_001099408.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4E1B	NM_001099408.2 link	c.584C>T	p.Ala195Val	missense_variant	Exon 8 of 9	ENST00000318682.11	NP_001092878.1	A6NMX2
EIF4E1B	NM_001375362.1 link	c.584C>T	p.Ala195Val	missense_variant	Exon 8 of 9		NP_001362291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4E1B	ENST00000318682.11 link	c.584C>T	p.Ala195Val	missense_variant	Exon 8 of 9	5	NM_001099408.2	ENSP00000323714.6		A6NMX2
EIF4E1B	ENST00000504597.5 link	c.584C>T	p.Ala195Val	missense_variant	Exon 8 of 9	5		ENSP00000427633.1		A6NMX2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151874

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000233

AC:

AN:

171662

AF XY:

0.0000329

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000473

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

AN:

1361422

Hom.:

Cov.:

AF XY:

0.0000779

AC XY:

AN XY:

667464

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

29902

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

27488

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

20020

Gnomad4 EAS exome

AF:

0.0000264

AC:

AN:

37920

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

69150

Gnomad4 FIN exome

AF:

0.0000198

AC:

AN:

50504

Gnomad4 NFE exome

AF:

0.0000873

AC:

AN:

1065062

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

56072

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

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:

0.0000294

AC:

0.0000294291

AN:

0.0000294291

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.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.584C>T (p.A195V) alteration is located in exon 8 (coding exon 6) of the EIF4E1B gene. This alteration results from a C to T substitution at nucleotide position 584, causing the alanine (A) at amino acid position 195 to be replaced by a valine (V). 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

0.27

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;T;T

Eigen

Benign

0.047

Eigen_PC

Benign

-0.048

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.65

.;T;.

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.5

M;M;M

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.0

.;N;N

REVEL

Benign

0.17

Sift

Benign

0.12

.;T;T

Sift4G

Benign

0.25

.;T;T

Polyphen

0.91

P;P;P

Vest4

0.61, 0.61

MutPred

0.77

Gain of MoRF binding (P = 0.0912);Gain of MoRF binding (P = 0.0912);Gain of MoRF binding (P = 0.0912);

MVP

0.74

MPC

0.85

ClinPred

0.75

GERP RS

4.3

Varity_R

0.062

gMVP

0.40

Mutation Taster

=67/33

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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