3-184321878-A-G

Variant names:

• chr3-184321878-A-G
• rs2178403
• NM_198241.3:c.1294A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 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, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.682
• Publications: 57 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 518344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EIF4G1	NM_198241.3	c.1294A>G	p.Met432Val	missense_variant	Exon 10 of 33	ENST00000346169.7	NP_937884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4G1	ENST00000346169.7	c.1294A>G	p.Met432Val	missense_variant	Exon 10 of 33	1	NM_198241.3	ENSP00000316879.5

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

GnomAD2 exomes AF: 0.755 AC: 189823 AN: 251318 AF XY: 0.746

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 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

African (AFR) AF: 0.962 AC: 32210 AN: 33480

American (AMR) AF: 0.822 AC: 36781 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 21637 AN: 26134

East Asian (EAS) AF: 0.649 AC: 25784 AN: 39700

South Asian (SAS) AF: 0.672 AC: 57977 AN: 86258

European-Finnish (FIN) AF: 0.697 AC: 37192 AN: 53398

Middle Eastern (MID) AF: 0.819 AC: 4722 AN: 5768

European-Non Finnish (NFE) AF: 0.745 AC: 828981 AN: 1111992

Other (OTH) AF: 0.761 AC: 45954 AN: 60396

GnomAD4 genome AF: 0.799 AC: 121630 AN: 152140 Hom.: 49515 Cov.: 32 AF XY: 0.791 AC XY: 58826 AN XY: 74346

African (AFR) AF: 0.954 AC: 39622 AN: 41542

American (AMR) AF: 0.809 AC: 12361 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2862 AN: 3472

East Asian (EAS) AF: 0.647 AC: 3339 AN: 5158

South Asian (SAS) AF: 0.667 AC: 3213 AN: 4818

European-Finnish (FIN) AF: 0.688 AC: 7271 AN: 10576

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.744 AC: 50551 AN: 67986

Other (OTH) AF: 0.810 AC: 1711 AN: 2112

Alfa AF: 0.772 Hom.: 130472

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

Submissions by phenotype

not specified Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Parkinson disease 18, autosomal dominant, susceptibility to Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.;.;.;.;.;.;.
PhyloP100		0.68
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
Vest4		0.010
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2178403; hg19: chr3-184039666; COSMIC: COSV100072303; COSMIC: COSV100072303;