Genetic Variant FLI1:c.-646_-635dupGAGAGAGAGAGA (chr11-128693941-C-CGAGAGAGAGAGA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The ENST00000281428.12(FLI1):c.-646_-635dupGAGAGAGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.00037 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00037 ( 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: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000374 (31/82830) while in subpopulation AFR AF = 0.000543 (10/18426). AF 95% confidence interval is 0.000294. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

82806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000544

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000128

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000430

Gnomad OTH

AF:

0.000864

GnomAD4 exome

AF:

0.000373

AC:

AN:

93832

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

AN XY:

44550

show subpopulations

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

African (AFR)

AF:

0.000761

AC:

AN:

3944

American (AMR)

AF:

0.00109

AC:

AN:

2754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5370

East Asian (EAS)

AF:

0.0000862

AC:

AN:

11600

South Asian (SAS)

AF:

0.00

AC:

AN:

1776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1998

Middle Eastern (MID)

AF:

0.00174

AC:

AN:

574

European-Non Finnish (NFE)

AF:

0.000462

AC:

AN:

58404

Other (OTH)

AF:

0.00

AC:

AN:

7412

⚠️ 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: 0.269

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000374

AC:

AN:

82830

Hom.:

Cov.:

AF XY:

0.000445

AC XY:

AN XY:

38178

show subpopulations

African (AFR)

AF:

0.000543

AC:

AN:

18426

American (AMR)

AF:

0.000128

AC:

AN:

7832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2484

East Asian (EAS)

AF:

0.00

AC:

AN:

2702

South Asian (SAS)

AF:

0.00

AC:

AN:

2114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.000430

AC:

AN:

44216

Other (OTH)

AF:

0.000853

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over