Genetic Variant FLI1:c.-648_-635delGAGAGAGAGAGAGA (chr11-128693941-CGAGAGAGAGAGAGA-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The ENST00000281428.12(FLI1):c.-648_-635delGAGAGAGAGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 176,128 control chromosomes in the GnomAD database, including 63 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.038 ( 63 hom., cov: 0)

Exomes 𝑓: 0.034 ( 0 hom. )

Consequence

FLI1
ENST00000281428.12 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLI1	NM_002017.5 link	c.-317_-304delGAGAGAGAGAGAGA		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_-304delGAGAGAGAGAGAGA		upstream_gene_variant		1	NM_002017.5	ENSP00000433488.2		Q01543-1

Frequencies

GnomAD3 genomes

AF:

0.0382

AC:

3159

AN:

82798

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0230

Gnomad AMI

AF:

0.0583

Gnomad AMR

AF:

0.0468

Gnomad ASJ

AF:

0.0374

Gnomad EAS

AF:

0.0111

Gnomad SAS

AF:

0.0602

Gnomad FIN

AF:

0.0195

Gnomad MID

AF:

0.0500

Gnomad NFE

AF:

0.0445

Gnomad OTH

AF:

0.0423

GnomAD4 exome

AF:

0.0339

AC:

3165

AN:

93306

Hom.:

AF XY:

0.0338

AC XY:

1497

AN XY:

44292

show subpopulations

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

African (AFR)

AF:

0.0242

AC:

AN:

3928

American (AMR)

AF:

0.0358

AC:

AN:

2734

Ashkenazi Jewish (ASJ)

AF:

0.0258

AC:

138

AN:

5348

East Asian (EAS)

AF:

0.0151

AC:

174

AN:

11514

South Asian (SAS)

AF:

0.0300

AC:

AN:

1766

European-Finnish (FIN)

AF:

0.0287

AC:

AN:

1986

Middle Eastern (MID)

AF:

0.0316

AC:

AN:

570

European-Non Finnish (NFE)

AF:

0.0391

AC:

2271

AN:

58084

Other (OTH)

AF:

0.0354

AC:

261

AN:

7376

⚠️ 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: 0.349

Heterozygous variant carriers

173

347

520

694

867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0382

AC:

3160

AN:

82822

Hom.:

Cov.:

AF XY:

0.0373

AC XY:

1422

AN XY:

38168

show subpopulations

African (AFR)

AF:

0.0230

AC:

423

AN:

18424

American (AMR)

AF:

0.0468

AC:

367

AN:

7838

Ashkenazi Jewish (ASJ)

AF:

0.0374

AC:

AN:

2484

East Asian (EAS)

AF:

0.0111

AC:

AN:

2700

South Asian (SAS)

AF:

0.0616

AC:

130

AN:

2110

European-Finnish (FIN)

AF:

0.0195

AC:

AN:

3178

Middle Eastern (MID)

AF:

0.0448

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0445

AC:

1967

AN:

44216

Other (OTH)

AF:

0.0418

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=93/7

polymorphism

(source)

Splicing

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

Publications

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11-128693941-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA-CGAGAGAGAGAGAGAGAGAGAGAGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over