NM_002017.5:c.18+8G>C

Variant names:

• chr11-128694284-G-C
• rs573220409
• NM_002017.5:c.18+8G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002017.5(FLI1):​c.18+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000817 in 1,223,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: FLI1 NM_002017.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004666
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• 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]

SENCR (HGNC:44177): (smooth muscle and endothelial cell enriched migration/differentiation-associated lncRNA)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLI1	NM_002017.5	MANE Select	c.18+8G>C		splice_region intron	N/A	NP_002008.2
	FLI1	NM_001167681.3		c.-136+8G>C		splice_region intron	N/A	NP_001161153.1	Q01543-3
	FLI1	NM_001440369.1		c.-82+1141G>C		intron	N/A	NP_001427298.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLI1	ENST00000527786.7	TSL:1 MANE Select	c.18+8G>C		splice_region intron	N/A	ENSP00000433488.2	Q01543-1
	FLI1	ENST00000429175.7	TSL:1	n.18+8G>C		splice_region intron	N/A	ENSP00000399985.3	A0A0A0MSR4
	SENCR	ENST00000526269.2	TSL:1	n.112-893C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.17e-7 AC: 1 AN: 1223734 Hom.: 0 Cov.: 31 AF XY: 0.00000168 AC XY: 1 AN XY: 594544

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

African (AFR) AF: 0.00 AC: 0 AN: 25352

American (AMR) AF: 0.00 AC: 0 AN: 18458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17138

East Asian (EAS) AF: 0.00 AC: 0 AN: 30498

South Asian (SAS) AF: 0.00 AC: 0 AN: 48092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4766

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 985854

Other (OTH) AF: 0.00 AC: 0 AN: 48836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		1.9
PromoterAI		-0.0024	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.020
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: rs573220409; hg19: chr11-128564179;