Genetic Variant EIF4G3:p.Met1383Thr (chr1-20829186-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001391906.1(EIF4G3):c.4148T>C(p.Met1383Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,978 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 16 hom. )

Consequence

EIF4G3
NM_001391906.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 8.84

Publications

2 publications found

Variant links:

Genes affected

EIF4G3 (HGNC:3298): (eukaryotic translation initiation factor 4 gamma 3) The protein encoded by this gene is thought to be part of the eIF4F protein complex, which is involved in mRNA cap recognition and transport of mRNAs to the ribosome. Interestingly, a microRNA (miR-520c-3p) has been found that negatively regulates synthesis of the encoded protein, and this leads to a global decrease in protein translation and cell proliferation. Therefore, this protein is a key component of the anti-tumor activity of miR-520c-3p. [provided by RefSeq, May 2016]

EIF4G3 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.009413511).

BP6

Variant 1-20829186-A-G is Benign according to our data. Variant chr1-20829186-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 786717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00687 (1046/152288) while in subpopulation AFR AF = 0.0241 (1002/41556). AF 95% confidence interval is 0.0229. There are 10 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001391906.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4G3	NM_001391906.1	MANE Select	c.4148T>C	p.Met1383Thr	missense	Exon 31 of 37	NP_001378835.1	A0A8J9G7U8
EIF4G3	NM_001391907.1		c.4238T>C	p.Met1413Thr	missense	Exon 31 of 37	NP_001378836.1
EIF4G3	NM_001438678.1		c.4127T>C	p.Met1376Thr	missense	Exon 30 of 36	NP_001425607.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4G3	ENST00000602326.6	TSL:1 MANE Select	c.4148T>C	p.Met1383Thr	missense	Exon 31 of 37	ENSP00000473510.2	A0A8J9G7U8
EIF4G3	ENST00000400422.6	TSL:1	c.4088T>C	p.Met1363Thr	missense	Exon 29 of 35	ENSP00000383274.2	A0A0A0MSA7
EIF4G3	ENST00000693470.1		c.4910T>C	p.Met1637Thr	missense	Exon 27 of 33	ENSP00000509295.1	A0A8I5KV92

Frequencies

GnomAD3 genomes

AF:

0.00685

AC:

1043

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00164

AC:

412

AN:

251140

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.0222

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000747

AC:

1092

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

479

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0257

AC:

859

AN:

33458

American (AMR)

AF:

0.00136

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111898

Other (OTH)

AF:

0.00224

AC:

135

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00687

AC:

1046

AN:

152288

Hom.:

Cov.:

AF XY:

0.00667

AC XY:

497

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0241

AC:

1002

AN:

41556

American (AMR)

AF:

0.00235

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

140

186

233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00253

Hom.:

Bravo

AF:

0.00814

ESP6500AA

AF:

0.0261

AC:

115

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00208

AC:

252

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.62

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

8.8

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.38

Sift

Uncertain

0.027

Sift4G

Benign

0.13

Polyphen

0.97

Vest4

0.66

MVP

0.18

MPC

0.90

ClinPred

0.038

GERP RS

5.7

Varity_R

0.52

gMVP

0.90

Mutation Taster

=55/45

polymorphism

(source)

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

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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