Genetic Variant EIF4G1:p.His1335Gln (chr3-184328682-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_198241.3(EIF4G1):c.4005C>A(p.His1335Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1335H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EIF4G1
NM_198241.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.34

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198241.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4G1	NM_198241.3	MANE Select	c.4005C>A	p.His1335Gln	missense	Exon 27 of 33	NP_937884.2	Q04637-1
EIF4G1	NM_001194946.2		c.4026C>A	p.His1342Gln	missense	Exon 28 of 34	NP_001181875.2	Q04637-9
EIF4G1	NM_001194947.2		c.4026C>A	p.His1342Gln	missense	Exon 27 of 33	NP_001181876.2	Q04637-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4G1	ENST00000346169.7	TSL:1 MANE Select	c.4005C>A	p.His1335Gln	missense	Exon 27 of 33	ENSP00000316879.5	Q04637-1
EIF4G1	ENST00000352767.7	TSL:1	c.4026C>A	p.His1342Gln	missense	Exon 27 of 33	ENSP00000338020.4	Q04637-9
EIF4G1	ENST00000382330.7	TSL:1	c.4026C>A	p.His1342Gln	missense	Exon 28 of 34	ENSP00000371767.3	Q04637-9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

8.7

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.49

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

3.2

PhyloP100

-1.3

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.43

Sift

Uncertain

0.012

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.77

MutPred

0.51

Gain of catalytic residue at H1335 (P = 0.0706)

MVP

0.73

MPC

1.2

ClinPred

0.99

GERP RS

-4.2

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.9

Varity_R

0.82

gMVP

0.66

Mutation Taster

=35/65

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over