Genetic Variant EIF4B:p.Pro514Gln (chr12-53038376-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001417.7(EIF4B):c.1541C>A(p.Pro514Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,600,444 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

EIF4B
NM_001417.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Variant links:

Genes affected

EIF4B (HGNC:3285): (eukaryotic translation initiation factor 4B) Enables RNA binding activity. Predicted to be involved in eukaryotic translation initiation factor 4F complex assembly and formation of translation preinitiation complex. Located in cytosol. Biomarker of autism spectrum disorder and major depressive disorder. [provided by Alliance of Genome Resources, Apr 2022]

EIF4B links:

TNS2-AS1 (HGNC:27464): (TNS2 antisense RNA 1)

TNS2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2953506).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4B	NM_001417.7 link	c.1541C>A	p.Pro514Gln	missense_variant	Exon 12 of 15	ENST00000262056.14	NP_001408.2	P23588-1
EIF4B	NM_001300821.3 link	c.1556C>A	p.Pro519Gln	missense_variant	Exon 12 of 15		NP_001287750.1	E7EX17B4DRM3Q7Z5Y0
EIF4B	NM_001330654.2 link	c.1424C>A	p.Pro475Gln	missense_variant	Exon 11 of 14		NP_001317583.1	P23588-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4B	ENST00000262056.14 link	c.1541C>A	p.Pro514Gln	missense_variant	Exon 12 of 15	1	NM_001417.7	ENSP00000262056.9		P23588-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152172

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1448272

Hom.:

Cov.:

AF XY:

0.00000833

AC XY:

AN XY:

720394

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

32842

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

43104

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25822

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

38784

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

84152

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53152

Gnomad4 NFE exome

AF:

0.0000136

AC:

AN:

1104984

Gnomad4 Remaining exome

AF:

0.0000167

AC:

AN:

59716

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:

0.0000197

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

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:

0.0000441

AC:

0.0000440956

AN:

0.0000440956

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:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1541C>A (p.P514Q) alteration is located in exon 12 (coding exon 12) of the EIF4B gene. This alteration results from a C to A substitution at nucleotide position 1541, causing the proline (P) at amino acid position 514 to be replaced by a glutamine (Q). 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

0.087

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.2

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.25

MutPred

0.30

.;Gain of sheet (P = 0.0028);.;

MVP

0.43

MPC

0.20

ClinPred

0.83

GERP RS

4.3

Varity_R

0.15

gMVP

0.15

Mutation Taster

=86/14

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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