rs111290936

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_198241.3(EIF4G1):c.1505C>T(p.Ala502Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

EIF4G1
NM_198241.3 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 1.74

Publications

27 publications found

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 Gene-Disease associations (from GenCC):

Parkinson disease 18, autosomal dominant, susceptibility to
Inheritance: Unknown, AD Classification: MODERATE, LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

EIF4G1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1090146).

BS2

High AC in GnomAd4 at 10 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G1	NM_198241.3 link	c.1505C>T	p.Ala502Val	missense_variant	Exon 10 of 33	ENST00000346169.7	NP_937884.2	Q04637-1Q96I65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G1	ENST00000346169.7 link	c.1505C>T	p.Ala502Val	missense_variant	Exon 10 of 33	1	NM_198241.3	ENSP00000316879.5		Q04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000724

AC:

AN:

248586

AF XY:

0.0000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000152

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1461664

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000116

AC:

129

AN:

1112012

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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

AF:

0.0000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000661

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Parkinson disease 18, autosomal dominant, susceptibility to

Other:1

Jan 01, 2015

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.068

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

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.83

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

M_CAP

Benign

0.0069

MetaRNN

Benign

0.11

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.64

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

PhyloP100

1.7

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.71

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

REVEL

Benign

0.21

Sift

Benign

0.24

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

Polyphen

0.0010

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

Vest4

0.18

MVP

0.97

MPC

0.069

ClinPred

0.023

GERP RS

3.9

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.2

Varity_R

0.068

gMVP

0.19

Mutation Taster

=0/100

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over