Genetic Variant FLI1:c.-642_-635dupGAGAGAGA (chr11-128693941-C-CGAGAGAGA) – 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.-642_-635dupGAGAGAGA 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 0.0047 ( 15 hom., cov: 0)

Exomes 𝑓: 0.0027 ( 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 afr. GnomAd4 allele frequency = 0.00475 (393/82814) while in subpopulation AFR AF = 0.00619 (114/18420). AF 95% confidence interval is 0.00527. There are 15 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

393

AN:

82790

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00621

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00230

Gnomad ASJ

AF:

0.000403

Gnomad EAS

AF:

0.00295

Gnomad SAS

AF:

0.00329

Gnomad FIN

AF:

0.00220

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00534

Gnomad OTH

AF:

0.00173

GnomAD4 exome

AF:

0.00267

AC:

250

AN:

93544

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

105

AN XY:

44432

show subpopulations

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

African (AFR)

AF:

0.00408

AC:

AN:

3926

American (AMR)

AF:

0.00219

AC:

AN:

2744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5364

East Asian (EAS)

AF:

0.00199

AC:

AN:

11574

South Asian (SAS)

AF:

0.000564

AC:

AN:

1774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1998

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

572

European-Non Finnish (NFE)

AF:

0.00315

AC:

183

AN:

58176

Other (OTH)

AF:

0.00256

AC:

AN:

7416

⚠️ 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: 0.283

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00475

AC:

393

AN:

82814

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

171

AN XY:

38162

show subpopulations

African (AFR)

AF:

0.00619

AC:

114

AN:

18420

American (AMR)

AF:

0.00230

AC:

AN:

7830

Ashkenazi Jewish (ASJ)

AF:

0.000403

AC:

AN:

2484

East Asian (EAS)

AF:

0.00296

AC:

AN:

2702

South Asian (SAS)

AF:

0.00331

AC:

AN:

2114

European-Finnish (FIN)

AF:

0.00220

AC:

AN:

3178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.00534

AC:

236

AN:

44214

Other (OTH)

AF:

0.00171

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

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-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

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