rs11734039

Positions:

• chr4-53398261-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030917.4(FIP1L1):​c.706-1469T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 151,984 control chromosomes in the GnomAD database, including 25,313 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25313 hom., cov: 31)
• Consequence: FIP1L1 NM_030917.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800

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]

ENSG00000282278 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIP1L1	NM_030917.4	c.706-1469T>C		intron_variant		ENST00000337488.11	NP_112179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIP1L1	ENST00000337488.11	c.706-1469T>C		intron_variant		1	NM_030917.4	ENSP00000336752.6
ENSG00000282278	ENST00000507166.5	c.706-1469T>C		intron_variant		2		ENSP00000423325.1

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84433 AN: 151866 Hom.: 25314 Cov.: 31

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.723

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.582

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

GnomAD4 genome AF: 0.556 AC: 84466 AN: 151984 Hom.: 25313 Cov.: 31 AF XY: 0.556 AC XY: 41333 AN XY: 74284

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.634

Gnomad4 ASJ AF: 0.687

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.684

Gnomad4 NFE AF: 0.668

Gnomad4 OTH AF: 0.577

Alfa AF: 0.592 Hom.: 4185

Bravo AF: 0.547

Asia WGS AF: 0.434 AC: 1515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.78

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: rs11734039; hg19: chr4-54264428;