Genetic Variant EIF3B:p.Pro40Thr (chr7-2355039-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001037283.2(EIF3B):c.118C>A(p.Pro40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 149,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40S) has been classified as Uncertain significance.

Frequency

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

Consequence

EIF3B
NM_001037283.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.704

Variant links:

Genes affected

EIF3B (HGNC:3280): (eukaryotic translation initiation factor 3 subunit B) Enables RNA binding activity. Contributes to translation initiation factor activity. Involved in several processes, including IRES-dependent viral translational initiation; translational initiation; and viral translational termination-reinitiation. Located in extracellular exosome. Part of eukaryotic translation initiation factor 3 complex. [provided by Alliance of Genome Resources, Apr 2022]

EIF3B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074489266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF3B	NM_001037283.2 link	c.118C>A	p.Pro40Thr	missense_variant	Exon 1 of 19	ENST00000360876.9	NP_001032360.1	P55884-1A0A024R821

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EIF3B	ENST00000360876.9 link	c.118C>A	p.Pro40Thr	missense_variant	Exon 1 of 19	1	NM_001037283.2	ENSP00000354125.4	P55884-1
EIF3B	ENST00000397011.2 link	c.118C>A	p.Pro40Thr	missense_variant	Exon 1 of 19	1		ENSP00000380206.2	P55884-1
EIF3B	ENST00000413917.5 link	c.118C>A	p.Pro40Thr	missense_variant	Exon 1 of 7	2		ENSP00000407785.1	C9JZG1
EIF3B	ENST00000431643.5 link	c.-504-195C>A		intron_variant	Intron 1 of 7	5		ENSP00000408062.1	C9JQN7

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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

Cov.:

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149816

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

73120

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.118C>A (p.P40T) alteration is located in exon 1 (coding exon 1) of the EIF3B gene. This alteration results from a C to A substitution at nucleotide position 118, causing the proline (P) at amino acid position 40 to be replaced by a threonine (T). 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

0.070

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.019

T;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.50

.;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.074

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;L

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.025

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.014

B;.;B

Vest4

0.041

MutPred

0.29

Gain of phosphorylation at P40 (P = 0.0189);Gain of phosphorylation at P40 (P = 0.0189);Gain of phosphorylation at P40 (P = 0.0189);

MVP

0.24

MPC

0.42

ClinPred

0.077

GERP RS

1.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.8

Varity_R

0.042

gMVP

0.16

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