chr3-184321878-A-G

Position:

chr3-184321878-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_198241.3(EIF4G1):c.1294A>G(p.Met432Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 1,613,990 control chromosomes in the GnomAD database, including 458,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 49515 hom., cov: 32)

Exomes 𝑓: 0.75 ( 409186 hom. )

Consequence

EIF4G1
NM_198241.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.682

Variant links:

Genes affected

EIF4G1 (HGNC:3296): (eukaryotic translation initiation factor 4 gamma 1) The protein encoded by this gene is a component of the multi-subunit protein complex EIF4F. This complex facilitates the recruitment of mRNA to the ribosome, which is a rate-limiting step during the initiation phase of protein synthesis. The recognition of the mRNA cap and the ATP-dependent unwinding of 5'-terminal secondary structure is catalyzed by factors in this complex. The subunit encoded by this gene is a large scaffolding protein that contains binding sites for other members of the EIF4F complex. A domain at its N-terminus can also interact with the poly(A)-binding protein, which may mediate the circularization of mRNA during translation. Alternative splicing results in multiple transcript variants, some of which are derived from alternative promoter usage. [provided by RefSeq, Aug 2010]

EIF4G1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EIF4G1. . Gene score misZ 2.2233 (greater than the threshold 3.09). Trascript score misZ 4.0613 (greater than threshold 3.09). GenCC has associacion of gene with Parkinson disease 18, autosomal dominant, susceptibility to.

BP4

Computational evidence support a benign effect (MetaRNN=8.060675E-7).

BP6

Variant 3-184321878-A-G is Benign according to our data. Variant chr3-184321878-A-G is described in ClinVar as [Benign]. Clinvar id is 518344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184321878-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4G1	NM_198241.3 linkuse as main transcript	c.1294A>G	p.Met432Val	missense_variant	10/33	ENST00000346169.7	NP_937884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4G1	ENST00000346169.7 linkuse as main transcript	c.1294A>G	p.Met432Val	missense_variant	10/33	1	NM_198241.3	ENSP00000316879	A2	Q04637-1

Frequencies

GnomAD3 genomes

AF:

0.799

AC:

121520

AN:

152022

Hom.:

49455

Cov.:

show subpopulations

Gnomad AFR

AF:

0.954

Gnomad AMI

AF:

0.492

Gnomad AMR

AF:

0.809

Gnomad ASJ

AF:

0.824

Gnomad EAS

AF:

0.647

Gnomad SAS

AF:

0.667

Gnomad FIN

AF:

0.688

Gnomad MID

AF:

0.861

Gnomad NFE

AF:

0.744

Gnomad OTH

AF:

0.819

GnomAD3 exomes

AF:

0.755

AC:

189823

AN:

251318

Hom.:

72519

AF XY:

0.746

AC XY:

101341

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.954

Gnomad AMR exome

AF:

0.824

Gnomad ASJ exome

AF:

0.827

Gnomad EAS exome

AF:

0.657

Gnomad SAS exome

AF:

0.675

Gnomad FIN exome

AF:

0.694

Gnomad NFE exome

AF:

0.749

Gnomad OTH exome

AF:

0.763

GnomAD4 exome

AF:

0.746

AC:

1091238

AN:

1461850

Hom.:

409186

Cov.:

AF XY:

0.743

AC XY:

540385

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.962

Gnomad4 AMR exome

AF:

0.822

Gnomad4 ASJ exome

AF:

0.828

Gnomad4 EAS exome

AF:

0.649

Gnomad4 SAS exome

AF:

0.672

Gnomad4 FIN exome

AF:

0.697

Gnomad4 NFE exome

AF:

0.745

Gnomad4 OTH exome

AF:

0.761

GnomAD4 genome

AF:

0.799

AC:

121630

AN:

152140

Hom.:

49515

Cov.:

AF XY:

0.791

AC XY:

58826

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.954

Gnomad4 AMR

AF:

0.809

Gnomad4 ASJ

AF:

0.824

Gnomad4 EAS

AF:

0.647

Gnomad4 SAS

AF:

0.667

Gnomad4 FIN

AF:

0.688

Gnomad4 NFE

AF:

0.744

Gnomad4 OTH

AF:

0.810

Alfa

AF:

0.761

Hom.:

84991

Bravo

AF:

0.819

TwinsUK

AF:

0.750

AC:

2781

ALSPAC

AF:

0.748

AC:

2882

ESP6500AA

AF:

0.944

AC:

4159

ESP6500EA

AF:

0.758

AC:

6518

ExAC

AF:

0.755

AC:

91681

Asia WGS

AF:

0.680

AC:

2367

AN:

3478

EpiCase

AF:

0.752

EpiControl

AF:

0.760

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Parkinson disease 18, autosomal dominant, susceptibility to

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.074

DANN

Benign

0.34

DEOGEN2

Benign

0.039

T;.;.;.;.;T;.;T;.;T;.;.;.;T;.;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0049

LIST_S2

Benign

0.036

T;T;T;T;T;T;.;T;T;T;T;.;T;T;T;T;T;T

MetaRNN

Benign

8.1e-7

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.90

N;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

0.36

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.076

Sift

Benign

0.91

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.36

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.010

MPC

0.069

ClinPred

0.00040

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.12

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