dbSNP rs2230571: EIF4G1:p.His1335Gln (chr3-184328682-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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. 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

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G1	NM_198241.3 link	c.4005C>A	p.His1335Gln	missense_variant	Exon 27 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.4005C>A	p.His1335Gln	missense_variant	Exon 27 of 33	1	NM_198241.3	ENSP00000316879.5		Q04637-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

8.7

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

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

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.49

LIST_S2

Pathogenic

0.97

D;D;D;D;.;D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

3.2

M;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.4

D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.012

D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.;.;.;.;.;.;.

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

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over