3-184321878-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.682

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, EIF4G1
• 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_single_submitter, 1 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	UniProt
EIF4G1	NM_198241.3	c.1294A>G	p.Met432Val	missense_variant	10/33	ENST00000346169.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EIF4G1	ENST00000346169.7	c.1294A>G	p.Met432Val	missense_variant	10/33	1	NM_198241.3	A2

Frequencies

GnomAD3 genomes AF: 0.799 AC: 121520 AN: 152022 Hom.: 49455 Cov.: 32

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

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.: 89 AF XY: 0.743 AC XY: 540385 AN XY: 727224

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.: 32 AF XY: 0.791 AC XY: 58826 AN XY: 74346

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:4

Revision: criteria provided, single submitter

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	-	- -

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

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.60	T
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	N
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	T
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	T
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	T
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

Other links and lift over

dbSNP: rs2178403; hg19: chr3-184039666;