Genetic Variant FLI1:c.-654_-635delGAGAGAGAGAGAGAGAGAGA (chr11-128693941-CGAGAGAGAGAGAGAGAGAGA-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.-654_-635delGAGAGAGAGAGAGAGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 175,856 control chromosomes in the GnomAD database, including 13 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 0.011 ( 9 hom., cov: 0)

Exomes 𝑓: 0.050 ( 4 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 = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLI1	NM_002017.5 link	c.-317_-298delGAGAGAGAGAGAGAGAGAGA		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_-298delGAGAGAGAGAGAGAGAGAGA		upstream_gene_variant		1	NM_002017.5	ENSP00000433488.2		Q01543-1

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

905

AN:

82782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00871

Gnomad AMI

AF:

0.00177

Gnomad AMR

AF:

0.00319

Gnomad ASJ

AF:

0.0149

Gnomad EAS

AF:

0.00884

Gnomad SAS

AF:

0.0648

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.00714

Gnomad NFE

AF:

0.0103

Gnomad OTH

AF:

0.0112

GnomAD4 exome

AF:

0.0497

AC:

4622

AN:

93052

Hom.:

AF XY:

0.0506

AC XY:

2235

AN XY:

44188

show subpopulations

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

African (AFR)

AF:

0.0214

AC:

AN:

3934

American (AMR)

AF:

0.0299

AC:

AN:

2742

Ashkenazi Jewish (ASJ)

AF:

0.0632

AC:

334

AN:

5288

East Asian (EAS)

AF:

0.0389

AC:

449

AN:

11544

South Asian (SAS)

AF:

0.0469

AC:

AN:

1770

European-Finnish (FIN)

AF:

0.0811

AC:

161

AN:

1986

Middle Eastern (MID)

AF:

0.0594

AC:

AN:

572

European-Non Finnish (NFE)

AF:

0.0527

AC:

3048

AN:

57860

Other (OTH)

AF:

0.0472

AC:

347

AN:

7356

⚠️ 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: 0.348

Heterozygous variant carriers

266

531

797

1062

1328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0109

AC:

904

AN:

82804

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

438

AN XY:

38168

show subpopulations

African (AFR)

AF:

0.00874

AC:

161

AN:

18424

American (AMR)

AF:

0.00319

AC:

AN:

7830

Ashkenazi Jewish (ASJ)

AF:

0.0149

AC:

AN:

2484

East Asian (EAS)

AF:

0.00888

AC:

AN:

2702

South Asian (SAS)

AF:

0.0653

AC:

138

AN:

2114

European-Finnish (FIN)

AF:

0.0158

AC:

AN:

3170

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0103

AC:

456

AN:

44208

Other (OTH)

AF:

0.00939

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

107

142

178

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

=85/15

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-CGAGAGAGAGAGAGAGAGA

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