chr11-128810639-G-A

Variant names:

• chr11-128810639-G-A
• rs1064797086
• NM_002017.5:c.1010G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_002017.5(FLI1):​c.1010G>A​(p.Arg337Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R337W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLI1 NM_002017.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.94
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• bleeding disorder, platelet-type, 21

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-128810638-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 424632.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.4029 (below the threshold of 3.09). Trascript score misZ: 2.9534 (below the threshold of 3.09). GenCC associations: The gene is linked to bleeding disorder, platelet-type, 21.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 11-128810639-G-A is Pathogenic according to our data. Variant chr11-128810639-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 424635.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002017.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLI1	NM_002017.5	MANE Select	c.1010G>A	p.Arg337Gln	missense	Exon 9 of 9	NP_002008.2
	FLI1	NM_001167681.3		c.911G>A	p.Arg304Gln	missense	Exon 10 of 10	NP_001161153.1
	FLI1	NM_001440369.1		c.911G>A	p.Arg304Gln	missense	Exon 9 of 9	NP_001427298.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLI1	ENST00000527786.7	TSL:1 MANE Select	c.1010G>A	p.Arg337Gln	missense	Exon 9 of 9	ENSP00000433488.2
	FLI1	ENST00000281428.12	TSL:1	c.812G>A	p.Arg271Gln	missense	Exon 10 of 10	ENSP00000281428.8
	FLI1	ENST00000429175.7	TSL:1	n.*932G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000399985.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
1	-	-	11q partial monosomy syndrome (1)
1	-	-	Bleeding disorder, platelet-type, 21 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.83
Sift	Benign	0.076	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.94		Loss of MoRF binding (P = 0.0277)
MVP		0.97
MPC		2.3
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.97
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064797086; hg19: chr11-128680534;