Genetic Variant NM_001037283.2:c.98G>A (chr7-2355019-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001037283.2(EIF3B):c.98G>A(p.Gly33Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,035,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G33R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

EIF3B
NM_001037283.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.940

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04964274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037283.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF3B	NM_001037283.2	MANE Select	c.98G>A	p.Gly33Glu	missense	Exon 1 of 19	NP_001032360.1	P55884-1
EIF3B	NM_001362791.2		c.98G>A	p.Gly33Glu	missense	Exon 1 of 19	NP_001349720.1	P55884-1
EIF3B	NM_003751.4		c.98G>A	p.Gly33Glu	missense	Exon 1 of 19	NP_003742.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF3B	ENST00000360876.9	TSL:1 MANE Select	c.98G>A	p.Gly33Glu	missense	Exon 1 of 19	ENSP00000354125.4	P55884-1
EIF3B	ENST00000397011.2	TSL:1	c.98G>A	p.Gly33Glu	missense	Exon 1 of 19	ENSP00000380206.2	P55884-1
EIF3B	ENST00000899983.1		c.98G>A	p.Gly33Glu	missense	Exon 1 of 19	ENSP00000570042.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000193

AC:

AN:

1035022

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

489594

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21114

American (AMR)

AF:

0.00

AC:

AN:

6724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11958

East Asian (EAS)

AF:

0.00

AC:

AN:

21706

South Asian (SAS)

AF:

0.00

AC:

AN:

19500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2658

European-Non Finnish (NFE)

AF:

0.00000224

AC:

AN:

892120

Other (OTH)

AF:

0.00

AC:

AN:

39970

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.7

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.018

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00050

LIST_S2

Benign

0.44

M_CAP

Benign

0.044

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

0.94

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.31

REVEL

Benign

0.018

Sift

Benign

0.92

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.023

MutPred

0.22

Gain of helix (P = 0.0078)

MVP

0.13

MPC

0.48

ClinPred

0.076

GERP RS

2.0

PromoterAI

0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.027

gMVP

0.21

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over