Genetic Variant FLI1:c.-644_-635dupGAGAGAGAGA (chr11-128693941-C-CGAGAGAGAGA) – 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.-644_-635dupGAGAGAGAGA 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 0.0013 ( 3 hom., cov: 0)

Exomes 𝑓: 0.00083 ( 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 sas. GnomAd4 allele frequency = 0.00134 (111/82832) while in subpopulation SAS AF = 0.00236 (5/2116). AF 95% confidence interval is 0.0014. There are 3 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

112

AN:

82808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00190

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000766

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00110

Gnomad SAS

AF:

0.00281

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00714

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000864

GnomAD4 exome

AF:

0.000831

AC:

AN:

93816

Hom.:

Cov.:

AF XY:

0.000651

AC XY:

AN XY:

44548

show subpopulations

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

African (AFR)

AF:

0.00127

AC:

AN:

3938

American (AMR)

AF:

0.00109

AC:

AN:

2752

Ashkenazi Jewish (ASJ)

AF:

0.000559

AC:

AN:

5370

East Asian (EAS)

AF:

0.000690

AC:

AN:

11600

South Asian (SAS)

AF:

0.000565

AC:

AN:

1770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

574

European-Non Finnish (NFE)

AF:

0.000925

AC:

AN:

58400

Other (OTH)

AF:

0.000540

AC:

AN:

7414

⚠️ 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: 0.296

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00134

AC:

111

AN:

82832

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

AN XY:

38176

show subpopulations

African (AFR)

AF:

0.00190

AC:

AN:

18426

American (AMR)

AF:

0.000766

AC:

AN:

7830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2484

East Asian (EAS)

AF:

0.00111

AC:

AN:

2702

South Asian (SAS)

AF:

0.00236

AC:

AN:

2116

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

3184

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

44218

Other (OTH)

AF:

0.000853

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

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-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

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