Genetic Variant EIF4G1:c.324+107T>A (chr3-184317604-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198241.3(EIF4G1):c.324+107T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,546,262 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 123 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 125 hom. )

Consequence

EIF4G1
NM_198241.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.930

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 3-184317604-T-A is Benign according to our data. Variant chr3-184317604-T-A is described in ClinVar as Benign. ClinVar VariationId is 1227934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0748 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198241.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EIF4G1	NM_198241.3	MANE Select	c.324+107T>A	intron	N/A	NP_937884.2	Q04637-1
EIF4G1	NM_001194946.2		c.345+107T>A	intron	N/A	NP_001181875.2	Q04637-9
EIF4G1	NM_001194947.2		c.345+107T>A	intron	N/A	NP_001181876.2	Q04637-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EIF4G1	ENST00000346169.7	TSL:1 MANE Select	c.324+107T>A	intron	N/A	ENSP00000316879.5	Q04637-1
EIF4G1	ENST00000352767.7	TSL:1	c.345+107T>A	intron	N/A	ENSP00000338020.4	Q04637-9
EIF4G1	ENST00000382330.7	TSL:1	c.345+107T>A	intron	N/A	ENSP00000371767.3	Q04637-9

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3433

AN:

152226

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0771

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0248

GnomAD4 exome

AF:

0.00229

AC:

3190

AN:

1393918

Hom.:

125

Cov.:

AF XY:

0.00196

AC XY:

1364

AN XY:

695984

show subpopulations

African (AFR)

AF:

0.0797

AC:

2549

AN:

31982

American (AMR)

AF:

0.00456

AC:

190

AN:

41690

Ashkenazi Jewish (ASJ)

AF:

0.0000393

AC:

AN:

25468

East Asian (EAS)

AF:

0.00

AC:

AN:

39006

South Asian (SAS)

AF:

0.0000715

AC:

AN:

83866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52774

Middle Eastern (MID)

AF:

0.00319

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.000154

AC:

163

AN:

1055338

Other (OTH)

AF:

0.00452

AC:

263

AN:

58146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

168

337

505

674

842

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.0226

AC:

3439

AN:

152344

Hom.:

123

Cov.:

AF XY:

0.0215

AC XY:

1600

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0770

AC:

3199

AN:

41558

American (AMR)

AF:

0.0107

AC:

164

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68036

Other (OTH)

AF:

0.0246

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

167

334

500

667

834

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0148

Hom.:

Bravo

AF:

0.0262

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.93

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over