Genetic Variant FLI1:c.-640_-635dupGAGAGA (chr11-128693941-C-CGAGAGA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The ENST00000281428.12(FLI1):c.-640_-635dupGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0082 ( 21 hom., cov: 0)

Exomes 𝑓: 0.0060 ( 0 hom. )

Consequence

FLI1
ENST00000281428.12 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.709

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.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00823 (681/82792) while in subpopulation EAS AF = 0.01 (27/2698). AF 95% confidence interval is 0.00801. There are 21 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLI1	NM_002017.5 link	c.-318_-317insGAGAGA		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.-318_-317insGAGAGA		upstream_gene_variant		1	NM_002017.5	ENSP00000433488.2		Q01543-1

Frequencies

GnomAD3 genomes

AF:

0.00822

AC:

680

AN:

82770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00882

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00282

Gnomad EAS

AF:

0.00996

Gnomad SAS

AF:

0.00610

Gnomad FIN

AF:

0.00409

Gnomad MID

AF:

0.00725

Gnomad NFE

AF:

0.00873

Gnomad OTH

AF:

0.00604

GnomAD4 exome

AF:

0.00596

AC:

555

AN:

93160

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

253

AN XY:

44236

show subpopulations

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

African (AFR)

AF:

0.00718

AC:

AN:

3900

American (AMR)

AF:

0.00366

AC:

AN:

2734

Ashkenazi Jewish (ASJ)

AF:

0.00187

AC:

AN:

5352

East Asian (EAS)

AF:

0.0103

AC:

119

AN:

11506

South Asian (SAS)

AF:

0.00508

AC:

AN:

1772

European-Finnish (FIN)

AF:

0.000501

AC:

AN:

1996

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

566

European-Non Finnish (NFE)

AF:

0.00562

AC:

326

AN:

57984

Other (OTH)

AF:

0.00599

AC:

AN:

7350

⚠️ 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: 0.284

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00823

AC:

681

AN:

82792

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

303

AN XY:

38148

show subpopulations

African (AFR)

AF:

0.00890

AC:

164

AN:

18418

American (AMR)

AF:

0.00818

AC:

AN:

7824

Ashkenazi Jewish (ASJ)

AF:

0.00282

AC:

AN:

2484

East Asian (EAS)

AF:

0.0100

AC:

AN:

2698

South Asian (SAS)

AF:

0.00568

AC:

AN:

2114

European-Finnish (FIN)

AF:

0.00409

AC:

AN:

3180

Middle Eastern (MID)

AF:

0.00758

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.00873

AC:

386

AN:

44204

Other (OTH)

AF:

0.00597

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

110

137

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

0.71

Splicing

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

Publications

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11-128693941-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

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