11-128810619-GAATT-G

Variant names:

• chr11-128810619-GAATT-G
• rs1064797085
• NM_002017.5:c.992_995delATTA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002017.5(FLI1):​c.992_995delATTA​(p.Asn331ThrfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FLI1 NM_002017.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-128810619-GAATT-G is Pathogenic according to our data. Variant chr11-128810619-GAATT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 424634.Status of the report is no_assertion_criteria_provided, 0 stars.

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.992_995delATTA	p.Asn331ThrfsTer4	frameshift	Exon 9 of 9	NP_002008.2
	FLI1	NM_001167681.3		c.893_896delATTA	p.Asn298ThrfsTer4	frameshift	Exon 10 of 10	NP_001161153.1
	FLI1	NM_001440369.1		c.893_896delATTA	p.Asn298ThrfsTer4	frameshift	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.992_995delATTA	p.Asn331ThrfsTer4	frameshift	Exon 9 of 9	ENSP00000433488.2
	FLI1	ENST00000281428.12	TSL:1	c.794_797delATTA	p.Asn265ThrfsTer4	frameshift	Exon 10 of 10	ENSP00000281428.8
	FLI1	ENST00000429175.7	TSL:1	n.*914_*917delATTA		non_coding_transcript_exon	Exon 10 of 10	ENSP00000399985.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

May 01, 2020

Birmingham Platelet Group; University of Birmingham

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Thrombocytopenia Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Bleeding disorder, platelet-type, 21 Pathogenic:1

Apr 25, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=0/200	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: rs1064797085; hg19: chr11-128680514;