NM_030917.4:c.706-1469T>C

Variant names:

• chr4-53398261-T-C
• rs11734039
• NM_030917.4:c.706-1469T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030917.4. 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
	FIP1L1	NM_030917.4	MANE Select	c.706-1469T>C		intron	N/A	NP_112179.2
	FIP1L1	NM_001376744.1		c.706-1469T>C		intron	N/A	NP_001363673.1
	FIP1L1	NM_001376745.1		c.706-1469T>C		intron	N/A	NP_001363674.1	A0A994J6B4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FIP1L1	ENST00000337488.11	TSL:1 MANE Select	c.706-1469T>C		intron	N/A	ENSP00000336752.6	Q6UN15-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.706-1469T>C		intron	N/A	ENSP00000423325.1	A0A0B4J203
	FIP1L1	ENST00000306932.10	TSL:1	c.592-1469T>C		intron	N/A	ENSP00000302993.6	Q6UN15-3

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

African (AFR) AF: 0.323 AC: 13384 AN: 41442

American (AMR) AF: 0.634 AC: 9685 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2386 AN: 3472

East Asian (EAS) AF: 0.447 AC: 2312 AN: 5168

South Asian (SAS) AF: 0.430 AC: 2070 AN: 4816

European-Finnish (FIN) AF: 0.684 AC: 7216 AN: 10550

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.668 AC: 45377 AN: 67958

Other (OTH) AF: 0.577 AC: 1215 AN: 2104

Alfa AF: 0.520 Hom.: 8992

Bravo AF: 0.547

Asia WGS AF: 0.434 AC: 1515 AN: 3478

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	0.78
PhyloP100		-0.0080
Mutation Taster		=100/0	polymorphism (auto)

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: rs11734039; hg19: chr4-54264428;