chr3-184328682-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_198241.3(EIF4G1):c.4005C>T(p.His1335His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,962 control chromosomes in the GnomAD database, including 44,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2938 hom., cov: 32)

Exomes 𝑓: 0.23 ( 41589 hom. )

Consequence

EIF4G1
NM_198241.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.34

Publications

28 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 3-184328682-C-T is Benign according to our data. Variant chr3-184328682-C-T is described in ClinVar as Benign. ClinVar VariationId is 1210032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4G1	NM_198241.3 link	c.4005C>T	p.His1335His	synonymous_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>T	p.His1335His	synonymous_variant	Exon 27 of 33	1	NM_198241.3	ENSP00000316879.5		Q04637-1

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26456

AN:

152002

Hom.:

2934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0576

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.0497

Gnomad SAS

AF:

0.275

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.201

GnomAD2 exomes

AF:

0.199

AC:

50128

AN:

251484

AF XY:

0.210

show subpopulations

Gnomad AFR exome

AF:

0.0525

Gnomad AMR exome

AF:

0.120

Gnomad ASJ exome

AF:

0.246

Gnomad EAS exome

AF:

0.0521

Gnomad FIN exome

AF:

0.132

Gnomad NFE exome

AF:

0.252

Gnomad OTH exome

AF:

0.218

GnomAD4 exome

AF:

0.231

AC:

337749

AN:

1461842

Hom.:

41589

Cov.:

AF XY:

0.233

AC XY:

169748

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0481

AC:

1612

AN:

33480

American (AMR)

AF:

0.123

AC:

5523

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6349

AN:

26136

East Asian (EAS)

AF:

0.0365

AC:

1447

AN:

39696

South Asian (SAS)

AF:

0.279

AC:

24031

AN:

86254

European-Finnish (FIN)

AF:

0.137

AC:

7308

AN:

53420

Middle Eastern (MID)

AF:

0.277

AC:

1598

AN:

5768

European-Non Finnish (NFE)

AF:

0.248

AC:

276258

AN:

1111974

Other (OTH)

AF:

0.226

AC:

13623

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

15661

31322

46983

62644

78305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9170

18340

27510

36680

45850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.174

AC:

26456

AN:

152120

Hom.:

2938

Cov.:

AF XY:

0.168

AC XY:

12496

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.0575

AC:

2388

AN:

41536

American (AMR)

AF:

0.169

AC:

2575

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

835

AN:

3472

East Asian (EAS)

AF:

0.0496

AC:

257

AN:

5178

South Asian (SAS)

AF:

0.276

AC:

1328

AN:

4806

European-Finnish (FIN)

AF:

0.130

AC:

1370

AN:

10568

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.249

AC:

16949

AN:

67964

Other (OTH)

AF:

0.198

AC:

418

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1056

2112

3168

4224

5280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.227

Hom.:

15235

Bravo

AF:

0.168

Asia WGS

AF:

0.187

AC:

654

AN:

3478

EpiCase

AF:

0.259

EpiControl

AF:

0.256

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.1

(source)

DANN

Benign

0.83

PhyloP100

-1.3

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.9

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over