Genetic Variant FLI1:c.-636_-635dupGA (chr11-128693941-C-CGA) – 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.-636_-635dupGA 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 0.024 ( 94 hom., cov: 0)

Exomes 𝑓: 0.016 ( 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 = 0.0243 (2008/82708) while in subpopulation EAS AF = 0.0342 (92/2694). AF 95% confidence interval is 0.0285. There are 94 homozygotes in GnomAd4. There are 919 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 94 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

2009

AN:

82684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0292

Gnomad AMI

AF:

0.0372

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.0351

Gnomad SAS

AF:

0.0198

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.0143

Gnomad NFE

AF:

0.0230

Gnomad OTH

AF:

0.0242

GnomAD4 exome

AF:

0.0165

AC:

1515

AN:

91988

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

716

AN XY:

43694

show subpopulations

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

African (AFR)

AF:

0.0211

AC:

AN:

3838

American (AMR)

AF:

0.0137

AC:

AN:

2698

Ashkenazi Jewish (ASJ)

AF:

0.0257

AC:

135

AN:

5250

East Asian (EAS)

AF:

0.0262

AC:

296

AN:

11298

South Asian (SAS)

AF:

0.0119

AC:

AN:

1764

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

1992

Middle Eastern (MID)

AF:

0.0159

AC:

AN:

566

European-Non Finnish (NFE)

AF:

0.0144

AC:

825

AN:

57304

Other (OTH)

AF:

0.0144

AC:

105

AN:

7278

⚠️ 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: 0.287

Heterozygous variant carriers

126

253

379

506

632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0243

AC:

2008

AN:

82708

Hom.:

Cov.:

AF XY:

0.0241

AC XY:

919

AN XY:

38102

show subpopulations

African (AFR)

AF:

0.0292

AC:

538

AN:

18394

American (AMR)

AF:

0.0174

AC:

136

AN:

7814

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

AN:

2480

East Asian (EAS)

AF:

0.0341

AC:

AN:

2694

South Asian (SAS)

AF:

0.0194

AC:

AN:

2108

European-Finnish (FIN)

AF:

0.0119

AC:

AN:

3184

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

134

European-Non Finnish (NFE)

AF:

0.0230

AC:

1017

AN:

44164

Other (OTH)

AF:

0.0239

AC:

AN:

1172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

144

217

289

361

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-CGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGAGA

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