rs139830377

chr11-128810806-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002017.5(FLI1):c.1177G>A(p.Ala393Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,613,968 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A393V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (6 hom.)
• Consequence: FLI1 NM_002017.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.893

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008373201).
• BP6: Variant 11-128810806-G-A is Benign according to our data. Variant chr11-128810806-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000571 (87/152262) while in subpopulation EAS AF= 0.00887 (46/5184). AF 95% confidence interval is 0.00684. There are 1 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLI1	NM_002017.5	c.1177G>A	p.Ala393Thr	missense_variant	9/9	ENST00000527786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLI1	ENST00000527786.7	c.1177G>A	p.Ala393Thr	missense_variant	9/9	1	NM_002017.5	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152144 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00135 AC: 337 AN: 249324 Hom.: 2 AF XY: 0.00114 AC XY: 154 AN XY: 135250

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00656

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000534 AC: 781 AN: 1461706 Hom.: 6 Cov.: 32 AF XY: 0.000496 AC XY: 361 AN XY: 727134

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0116

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152262 Hom.: 1 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00887

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000534 Hom.: 1

Bravo AF: 0.000759

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00127 AC: 154

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 15, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	13
Dann	Benign	0.89
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.33	T
REVEL	Benign	0.026
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;.
Vest4		0.052
MVP		0.28
MPC		0.93
ClinPred		0.00030	T
GERP RS		2.0
Varity_R		0.019
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139830377; hg19: chr11-128680701;