Genetic Variant FLI1:c.-642_-635delGAGAGAGA (chr11-128693941-CGAGAGAGA-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The ENST00000281428.12(FLI1):c.-642_-635delGAGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0545 in 174,414 control chromosomes in the GnomAD database, including 103 homozygotes. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.041 ( 101 hom., cov: 0)

Exomes 𝑓: 0.067 ( 2 hom. )

Consequence

FLI1
ENST00000281428.12 5_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.53

Publications

0 publications found

Variant links:

Genes affected

FLI1 (HGNC:3749): (Fli-1 proto-oncogene, ETS transcription factor) This gene encodes a transcription factor containing an ETS DNA-binding domain. The gene can undergo a t(11;22)(q24;q12) translocation with the Ewing sarcoma gene on chromosome 22, which results in a fusion gene that is present in the majority of Ewing sarcoma cases. An acute lymphoblastic leukemia-associated t(4;11)(q21;q23) translocation involving this gene has also been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

FLI1 links:

SENCR (HGNC:44177): (smooth muscle and endothelial cell enriched migration/differentiation-associated lncRNA)

SENCR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 11-128693941-CGAGAGAGA-C is Benign according to our data. Variant chr11-128693941-CGAGAGAGA-C is described in ClinVar as [Benign]. Clinvar id is 1232949.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLI1	NM_002017.5 link	c.-317_-310delGAGAGAGA		upstream_gene_variant		ENST00000527786.7	NP_002008.2	Q01543-1A0A024R3M5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLI1	ENST00000527786.7 link	c.-317_-310delGAGAGAGA		upstream_gene_variant		1	NM_002017.5	ENSP00000433488.2		Q01543-1

Frequencies

GnomAD3 genomes

AF:

0.0409

AC:

3385

AN:

82750

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0899

Gnomad AMI

AF:

0.00177

Gnomad AMR

AF:

0.0322

Gnomad ASJ

AF:

0.0246

Gnomad EAS

AF:

0.0772

Gnomad SAS

AF:

0.0371

Gnomad FIN

AF:

0.0611

Gnomad MID

AF:

0.00714

Gnomad NFE

AF:

0.0202

Gnomad OTH

AF:

0.0363

GnomAD4 exome

AF:

0.0667

AC:

6116

AN:

91640

Hom.:

AF XY:

0.0639

AC XY:

2780

AN XY:

43534

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.110

AC:

422

AN:

3822

American (AMR)

AF:

0.0664

AC:

179

AN:

2694

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

287

AN:

5220

East Asian (EAS)

AF:

0.101

AC:

1132

AN:

11262

South Asian (SAS)

AF:

0.0428

AC:

AN:

1754

European-Finnish (FIN)

AF:

0.0785

AC:

154

AN:

1962

Middle Eastern (MID)

AF:

0.0461

AC:

AN:

564

European-Non Finnish (NFE)

AF:

0.0591

AC:

3378

AN:

57116

Other (OTH)

AF:

0.0639

AC:

463

AN:

7246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.316

Heterozygous variant carriers

397

794

1192

1589

1986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0409

AC:

3385

AN:

82774

Hom.:

101

Cov.:

AF XY:

0.0428

AC XY:

1635

AN XY:

38162

show subpopulations

African (AFR)

AF:

0.0897

AC:

1651

AN:

18410

American (AMR)

AF:

0.0323

AC:

253

AN:

7830

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

AN:

2484

East Asian (EAS)

AF:

0.0772

AC:

208

AN:

2694

South Asian (SAS)

AF:

0.0369

AC:

AN:

2116

European-Finnish (FIN)

AF:

0.0611

AC:

194

AN:

3176

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0203

AC:

895

AN:

44196

Other (OTH)

AF:

0.0368

AC:

AN:

1170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

121

243

364

486

607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 19, 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

PhyloP100

2.5

Mutation Taster

=298/2

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-128693941-CGAGAGAGA-C

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