4-53458645-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_030917.4(FIP1L1):c.1500-8A>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,606,916 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (29 hom.)
• Consequence: FIP1L1 NM_030917.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001790
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.22

Genes affected

FIP1L1 (HGNC:19124): (factor interacting with PAPOLA and CPSF1) This gene encodes a subunit of the CPSF (cleavage and polyadenylation specificity factor) complex that polyadenylates the 3' end of mRNA precursors. This gene, the homolog of yeast Fip1 (factor interacting with PAP), binds to U-rich sequences of pre-mRNA and stimulates poly(A) polymerase activity. Its N-terminus contains a PAP-binding site and its C-terminus an RNA-binding domain. An interstitial chromosomal deletion on 4q12 creates an in-frame fusion of human genes FIP1L1 and PDGFRA (platelet-derived growth factor receptor, alpha). The FIP1L1-PDGFRA fusion gene encodes a constitutively activated tyrosine kinase that joins the first 233 amino acids of FIP1L1 to the last 523 amino acids of PDGFRA. This gene fusion and chromosomal deletion is the cause of some forms of idiopathic hypereosinophilic syndrome (HES). This syndrome, recently reclassified as chronic eosinophilic leukemia (CEL), is responsive to treatment with tyrosine kinase inhibitors. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-53458645-A-C is Benign according to our data. Variant chr4-53458645-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2654756.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIP1L1	NM_030917.4	c.1500-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000337488.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIP1L1	ENST00000337488.11	c.1500-8A>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_030917.4	P4

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 608 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00615

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00436 AC: 1077 AN: 246990 Hom.: 7 AF XY: 0.00444 AC XY: 593 AN XY: 133578

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00186

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00668

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00485 AC: 7048 AN: 1454648 Hom.: 29 Cov.: 30 AF XY: 0.00478 AC XY: 3461 AN XY: 723492

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.00543

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.00400 AC: 609 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00383 AC XY: 285 AN XY: 74470

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00615

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00433 Hom.: 0

Bravo AF: 0.00427

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

FIP1L1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.074
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0040
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: rs191202834; hg19: chr4-54324812;