chr4-53391488-A-T

Variant names:

• chr4-53391488-A-T
• rs151072018
• NM_030917.4:c.695A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030917.4(FIP1L1):​c.695A>T​(p.Asn232Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,172 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N232S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FIP1L1 NM_030917.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.695A>T	p.Asn232Ile	missense	Exon 9 of 18	NP_112179.2
	FIP1L1	NM_001376744.1		c.695A>T	p.Asn232Ile	missense	Exon 9 of 19	NP_001363673.1
	FIP1L1	NM_001376745.1		c.695A>T	p.Asn232Ile	missense	Exon 9 of 19	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.695A>T	p.Asn232Ile	missense	Exon 9 of 18	ENSP00000336752.6	Q6UN15-1
	ENSG00000282278	ENST00000507166.5	TSL:2	c.695A>T	p.Asn232Ile	missense	Exon 9 of 24	ENSP00000423325.1	A0A0B4J203
	FIP1L1	ENST00000507922.5	TSL:1	c.650A>T	p.Asn217Ile	missense	Exon 8 of 12	ENSP00000425456.1	Q6UN15-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460172 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726550

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110594

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.7
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.098
Sift	Benign	0.077	T
Sift4G	Uncertain	0.023	D
Polyphen		0.94	P
Vest4		0.66
MutPred		0.46		Gain of sheet (P = 0.0011)
MVP		0.60
MPC		1.1
ClinPred		0.70	D
GERP RS		4.6
Varity_R		0.13
gMVP		0.33
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs151072018; hg19: chr4-54257655;