chr3-184319745-A-G

Position:

• chr3-184319745-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.481A>G​(p.Thr161Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,608,254 control chromosomes in the GnomAD database, including 799,127 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 1.0 (75806 hom., cov: 31)
  • Exomes 𝑓: 1.0 (723321 hom.)
• Consequence: EIF4G1 NM_198241.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.747

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EIF4G1. . Gene score misZ 2.2233 (greater than the threshold 3.09). Trascript score misZ 4.0613 (greater than threshold 3.09). GenCC has associacion of gene with Parkinson disease 18, autosomal dominant, susceptibility to.
• BP4: Computational evidence support a benign effect (MetaRNN=5.539281E-7).
• BP6: Variant 3-184319745-A-G is Benign according to our data. Variant chr3-184319745-A-G is described in ClinVar as [Benign]. Clinvar id is 1174883.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-184319745-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EIF4G1	NM_198241.3	c.481A>G	p.Thr161Ala	missense_variant	7/33	ENST00000346169.7	NP_937884.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EIF4G1	ENST00000346169.7	c.481A>G	p.Thr161Ala	missense_variant	7/33	1	NM_198241.3	ENSP00000316879.5

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151798 AN: 152104 Hom.: 75747 Cov.: 31

Gnomad AFR AF: 0.999

Gnomad AMI AF: 0.997

Gnomad AMR AF: 1.00

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.997

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.999

GnomAD3 exomes AF: 0.998 AC: 239825 AN: 240302 Hom.: 119676 AF XY: 0.998 AC XY: 129774 AN XY: 130056

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 0.997

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.997 AC: 1451328 AN: 1456032 Hom.: 723321 Cov.: 56 AF XY: 0.997 AC XY: 721286 AN XY: 723592

Gnomad4 AFR exome AF: 0.999

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 0.999

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.997

Gnomad4 NFE exome AF: 0.996

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.998 AC: 151916 AN: 152222 Hom.: 75806 Cov.: 31 AF XY: 0.998 AC XY: 74268 AN XY: 74402

Gnomad4 AFR AF: 0.999

Gnomad4 AMR AF: 1.00

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.997

Gnomad4 OTH AF: 0.999

Alfa AF: 0.998 Hom.: 90307

Bravo AF: 0.998

TwinsUK AF: 0.997 AC: 3698

ALSPAC AF: 0.998 AC: 3846

ESP6500AA AF: 0.999 AC: 4402

ESP6500EA AF: 0.996 AC: 8567

ExAC AF: 0.997 AC: 120710

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.9
DANN	Benign	0.81
DEOGEN2	Benign	0.063	T;.;.;.;.;T;.;T;.;T;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.092	T;T;T;T;T;T;.;T;T;T;T;.;T;T
MetaRNN	Benign	5.5e-7	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N;.;.;.;.;.;.;.;.;.;N;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.69	N;N;N;N;N;N;N;N;.;N;N;N;N;N
REVEL	Benign	0.036
Sift	Benign	1.0	T;T;T;T;T;T;T;T;.;T;T;T;T;T
Sift4G	Benign	0.93	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.034
MPC		0.63
ClinPred		0.0019	T
GERP RS		-1.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.050
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13319149; hg19: chr3-184037533;