11-128810639-G-A

Position:

• chr11-128810639-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 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. 13/21 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:3 U:1
• Conservation: PhyloP100: 9.94

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 12) in uniprot entity FLI1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_002017.5
• 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 id is 424632.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 id is 424635.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLI1	NM_002017.5	c.1010G>A	p.Arg337Gln	missense_variant	9/9	ENST00000527786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLI1	ENST00000527786.7	c.1010G>A	p.Arg337Gln	missense_variant	9/9	1	NM_002017.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 07, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 337 of the FLI1 protein (p.Arg337Gln). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLI1 protein function. ClinVar contains an entry for this variant (Variation ID: 424635). This missense change has been observed in individual(s) with clinical features of FLI1-related conditions (PMID: 28255014, 31064749). This variant is not present in population databases (gnomAD no frequency). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 14, 2020	DNA sequence analysis of the FLI1 gene demonstrated a sequence change, c.1010G>A, in exon 9 that results in an amino acid change, p.Arg337Gln. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Arg337Gln change has been reported in the heterozygous state in a family with macrothrombocytopenia. Functional analysis of this sequence change demonstrated a significant reduction in transcriptional activity (PMID: 28255014). The p.Arg337Gln change affects a highly conserved amino acid residue located in a domain of the FLI1 protein that is known to be functional. The p.Arg337Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -

Bleeding disorder, platelet-type, 21 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 25, 2017

- -

11q partial monosomy syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.5	.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;.;D;D
REVEL	Pathogenic	0.83
Sift	Benign	0.076	T;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;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

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: rs1064797086; hg19: chr11-128680534;